Dr. Betof Warner is a board-certified, fellowship-trained medical oncologist with the Cutaneous Oncology Program and an Assistant Professor in the Department of Medicine, Division of Medical Oncology. She also serves as Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and co-Director of the Pigmented Lesion and Melanoma Program.
Clinical interests of Dr. Betof Warner include treatment of advanced melanoma, immunotherapy, and cellular therapies for solid tumors. She has been a pioneer in the use of commercial tumor infiltrating lymphocyte (TIL) therapy, which is expected to become standard of care for immunotherapy-refractory melanoma.
Dr. Betof Warner serves as the leader of the Melanoma & Cutaneous Oncology Clinical Research Group, with research interests focused on tumor response to immunotherapy. She has been the principal investigator of multiple clinical trials focusing on immunotherapy-refractory melanoma and is internationally recognized for her expertise in central nervous system metastases and the use of novel cellular therapies. Dr. Betof Warner collaborates with investigators around the world in surgery, neuro-oncology, neurosurgery, radiation oncology, and pathology. She has received funding and awards for her clinical and translational investigative work from multiple high-profile organizations, including the American Society of Clinical Oncology (ASCO), National Institutes of Health (NIH), and Melanoma Research Foundation.
In addition to publishing her research in peer-reviewed journals, Dr. Betof Warner has served as an editorial and grant reviewer for multiple organizations, including the Melanoma Research Foundation. She has authored book chapters and case reports, contributed to national guidelines, and presented her findings at regional, national, and international meetings.
Dr. Betof Warner is a member of multiple professional organizations and societies, including the American Association for Cancer Research, the American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer, where she serves on the Early Career Scientist Committee. She is also a member of the American College of Sports Medicine and the European Society for Medical Oncology.
- Cellular Therapy
Fellowship: Memorial Sloan Kettering Cancer Center (2019) NY
Board Certification: American Board of Internal Medicine, Oncology (2018)
Board Certification: American Board of Internal Medicine, Internal Medicine (2016)
Residency: Massachusetts General Hospital Internal Medicine Residency (2016) MA
Medical Education: Duke University School of Medicine (2013) NC
Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers.
Seminars in neurology
Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.
View details for DOI 10.1055/s-0043-1776996
View details for PubMedID 37989214
The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.
European journal of cancer (Oxford, England : 1990)
2023; 196: 113441
Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown.Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated.299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001).Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.
View details for DOI 10.1016/j.ejca.2023.113441
View details for PubMedID 37988842
Exercise as an Immune Boost: Mechanism-Driven Support for Lifestyle Interventions.
Cancer immunology research
Modifiable host factors have demonstrated promise to enhance responses to immunotherapy. In this issue, Savage et al. investigated the use of aerobic exercise to enhance antitumor immunity in a murine model of melanoma. They show that treadmill running improves tumor vasculature and alters both T-cell and myeloid-cell infiltration of the tumor via an ERK5-dependent mechanism, adding to the growing evidence supporting the immune-mediated antitumor effects of exercise. See related article by Savage et al. (3).
View details for DOI 10.1158/2326-6066.CIR-23-0585
View details for PubMedID 37556587
CD4+ TIL to the rescue of anti-PD-1 failure by targeting MHC-II.
Clinical cancer research : an official journal of the American Association for Cancer Research
In this CCR Translations, we discuss the potential for tumor-infiltrating lymphocyte therapy to overcome immune-checkpoint inhibitor resistance through CD4+ mediated and MHCII dependent killing. Validating these results from human tumors has potential to improve the clinical application of adoptive cellular transfer in advanced cancers.
View details for DOI 10.1158/1078-0432.CCR-23-1333
View details for PubMedID 37534980
Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st-3rd, 2022-Naples, Italy).
Journal of translational medicine
2023; 21 (1): 508
Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st-3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.
View details for DOI 10.1186/s12967-023-04325-x
View details for PubMedID 37507765
View details for PubMedCentralID 5518563
A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for Web of Science ID 001053772005525
Real-world treatment patterns and outcomes for patients with advanced melanoma treated with immunotherapy or targeted therapy.
Pharmacoepidemiology and drug safety
To identify real-world patterns of first line treatment, treatment sequence and outcomes for older adults diagnosed with advanced melanoma who received immunotherapy or targeted therapy.The study population included older adults (ages 65+) diagnosed with unresectable or metastatic melanoma between 2012 and 2017 and who received first line immunotherapy or targeted therapy. Using the linked surveillance, epidemiology, and end results-medicare data, we described patterns of first line treatment and treatment sequence through 2018. We used descriptive statistics to report patient and provider characteristics by first line treatment receipt and changes in first line therapy use over calendar time. We also described overall survival (OS) and time to treatment failure (TTF) by first line treatment using the Kaplan-Meier method. For patterns of treatment sequence, we reported commonly observed treatment switch patterns by treatment sub-category and calendar year.The analyses included 584 patients (mean age = 76.3 years). A majority (n = 502) received first line immunotherapy. There was a sustained increase in immunotherapy uptake, most notably from 2015 to 2016. The estimated median OS and TTF were longer with first line immunotherapy than with targeted therapy. Individuals treated with CTLA-4 + PD-1 inhibitors had the longest median OS (28.4 months). The most common treatment switch pattern was from a first line CTLA-4 inhibitor to a second line PD-1 inhibitor.Our findings inform understanding of treatment patterns of currently used immunotherapies and targeted therapies in older adults with advanced melanoma. Immunotherapy use has increased steadily with PD-1 inhibitors becoming a dominant treatment option since 2015.
View details for DOI 10.1002/pds.5630
View details for PubMedID 37095605
Diversity, equity, and inclusion in the melanoma research community.
Pigment cell & melanoma research
The inaugural Diversity and Inclusion in Science Session was held during the 2021 Society for Melanoma Research (SMR) congress. The goal of the session was to discuss diversity, equity, and inclusion in the melanoma research community and strategies to promote the advancement of underrepresented melanoma researchers. An international survey was conducted to assess the diversity, equity, and inclusion (DEI) climate among researchers and clinicians within the Society for Melanoma Research (SMR). The findings suggest there are feelings and experiences of inequity, bias, and harassment within the melanoma community that correlate with one's gender, ethnic/racial group, and/or geographic location. Notably, significant reports of inequity in opportunity, discrimination, and sexual harassment demonstrate there is much work remaining to ensure all scientists in our community experience an academic workplace culture built on mutual respect, fair access, inclusion, and equitable opportunity.
View details for DOI 10.1111/pcmr.13087
View details for PubMedID 37093838
Beyond the 5-year milestone: Long-term survivorship of melanoma patients treated off-trial with anti-PD-1.
Pigment cell & melanoma research
Little is known about the long-term outcomes of anti-PD-1 treated patients with melanoma beyond 5years, especially for patients treated off clinical trials. This retrospective cohort study includes patients with unresectable stage III/IV nonuveal melanoma treated with anti-PD-1 off-trial at Memorial Sloan Kettering Cancer Center between 2014 and 2017 who survived at least 5years following their first anti-PD-1 dose (N=139). We characterized overall survival (OS), melanoma-specific survival (MSS) estimates, treatment-free survival rates, and subsequent treatment courses. Median follow-up among 5-plus year survivors (N=125) was 78.4months (range 60.0-96.3). OS at year 7 (2years post 5-year landmark) was 90.1% (95% CI: 83.0%-94.3%). Fourteen deaths occurred, seven due to melanoma. MSS at year 7 (2years post 5-year landmark) was 95.0% (95% CI: 33.5%-95.2%). In patients who completed anti-PD-1 based therapy and did not require subsequent treatment by 5years (N=80), the probability of not requiring additional treatment for an additional 2years was 95.7% (95% CI: 91.0%-100%). Patients treated with anti-PD-1 regimens off clinical trials who survive at least 5years from initial anti-PD-1 treatment can be reassured of their excellent long-term prognosis, particularly if they did not require additional melanoma treatment during the first 5years.
View details for DOI 10.1111/pcmr.13083
View details for PubMedID 37039320
T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants.
2023; 186 (7): 1432-1447.e17
Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.
View details for DOI 10.1016/j.cell.2023.03.007
View details for PubMedID 37001503
- Neoadjuvant relatlimab and nivolumab in resectable melanoma (vol 611, pg 155, 2022) NATURE 2023: E23
Efficacy of immunotherapy for melanoma brain metastases in patients with concurrent corticosteroid exposure.
2023; 12 (1): CNS93
Aim: Immune checkpoint inhibitor (ICI) efficacy is undefined for melanoma brain metastases (MBM) with concurrent corticosteroid exposure. Materials & methods: We retrospectively evaluated patients with untreated MBM who received corticosteroids (≥1.5 mg dexamethasone equivalent) within 30 days of ICI. mRECIST criteria and Kaplan-Meier methods defined intracranial progression-free survival (iPFS). The lesion size-response association was evaluated with repeated measures modeling. Results: A total of 109 MBM were evaluated. The patient level intracranial response rate was 41%. Median iPFS was 2.3 months and overall survival was 13.4 months. Larger lesions were more likely to progress, with diameter >2.05 cm most predictive of progression (OR: 18.9; 95% CI: 2.6-139.5; p = 0.004). There was no difference in iPFS with steroid exposure pre- versus post-ICI initiation. Conclusion: In the largest reported ICI+corticosteroid cohort, we identify size dependent MBM response.
View details for DOI 10.2217/cns-2022-0014
View details for PubMedID 36802833
View details for PubMedCentralID PMC9996406
Decision-Making and Health-Related Quality of Life in Patients with Melanoma Considering Adjuvant Immunotherapy
Adjuvant anti-PD1 treatment improves relapse-free survival (RFS) but has not been shown to improve overall survival (OS) in melanoma and is associated with risks of immune-related adverse events (irAEs), some permanent. We identified factors patients consider in deciding whether to undergo adjuvant anti-PD1 treatment and assessed prospective health-related quality of life (HRQoL), treatment satisfaction, and decisional regret.Patients with stage IIIB-IV cutaneous melanoma and free of disease, were candidates for adjuvant anti-PD1 immunotherapy, and had not yet discussed adjuvant treatment options with their oncologist were eligible. Participants viewed a 4-minute informational video tailored to their disease stage which communicated comprehensive, quantitative information about the risk of relapse both with and without adjuvant treatment, and risks of each irAE before deciding whether or not to opt for adjuvant therapy. We collected data on demographics, HRQoL, and attitudes toward adjuvant treatment over 1 year.14/34 patients (41%) opted for adjuvant anti-PD1 immunotherapy, 20/34 (59%) opted for observation. Patients choosing adjuvant immunotherapy scored higher on HRQoL social well-being at pre-treatment, were more likely to endorse positive statements about adjuvant immunotherapy, and to perceive that their physician preferred adjuvant therapy. They had lower decisional regret and higher satisfaction, even if they experienced toxicity or recurrence.When provided with comprehensive quantitative information about risks and benefits of adjuvant anti-PD1 immunotherapy, 20/34 (59%) of patients opted for observation. Patients choosing adjuvant immunotherapy had lower decisional regret and higher satisfaction over time even if they had poorer outcomes in treatment.
View details for DOI 10.1093/oncolo/oyac266
View details for Web of Science ID 000926203900001
View details for PubMedID 36745014
Real-world outcomes of different lines and sequences of treatment in BRAF-positive advanced melanoma patients.
2023; 33 (1): 38-49
The objective of this study is to compare efficacy with different treatment sequences and lines of treatment among BRAF V600 mutated (BRAF+) advanced melanoma patients with immunotherapies (IO) and targeted therapies (TT) using real-world data. This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational database, the harmonized customized data from Flatiron and ConcertAI. The study included BRAF+ advanced unresectable melanoma patients treated with first-line (1L) IO or TT between 1 January 2014 and 31 May 2020. Patient characteristics and treatment patterns were described. Kaplan-Meier curves and propensity score-adjusted Cox models were used for analyzing progression-free survival (PFS) and overall survival (OS). A total of 1961 patients were included, of which, 57.2% received IO and 42.8% received TT on 1L therapy. Overall, 603 patients initiated a 2L therapy: 56.2% IO and 43.8% TT. Regardless of treatment sequence, patients progressed at a relatively similar rate with no significant difference between groups (median PFS: 12.9 months for 1L TT/2L IO and 13.1 months for 1L IO/2L TT; HR, 0.84; P = 0.137). The 2-year OS rate was also similar with 1L TT/2L IO and 1L IO/2L TT (78% vs. 80%; HR, 1.09; P = 0.730). PFS was worse on 2L therapy compared with 1L (median 4.7 vs. 6.5 months). Efficacy on 2L therapy was poor compared with 1L. Among patients who received 2L therapy, regardless of treatment sequences, outcomes were comparable between 1L TT/2L IO and 1L IO/2L TT in this study that reflects real-world experiences beyond clinical trial selective eligibility criteria.
View details for DOI 10.1097/CMR.0000000000000856
View details for PubMedID 36545921
Metformin is associated with improved clinical outcomes in patients with melanoma: a retrospective, multi-institutional study.
Frontiers in oncology
2023; 13: 1075823
Background: Pre-clinical studies have shown that metformin reduces intratumoral hypoxia, improves T-cell function, and increases sensitivity to PD-1 blockade, and metformin exposure has been associated with improved clinical outcomes in various types of cancer. However, the impact of this drug in diabetic melanoma patients has not yet been fully elucidated.Methods: We reviewed 4,790 diabetic patients with stage I-IV cutaneous melanoma treated at the UPMC-Hillman Cancer Center and Memorial Sloan Kettering Cancer Center between 1996-2020. The primary endpoints included recurrence rates, progression free survival (PFS), and overall survival (OS) with and without metformin exposure. Tabulated variables included BRAF mutational status, immunotherapy (IMT) by type, and incidence of brain metastases.Results: The five-year incidence of recurrence in stage I/II patients was significantly reduced with metformin exposure (32.3% vs 47.7%, p=0.012). The five-year recurrence rate for stage III patients was also significantly reduced (58.3% vs 77.3%, p=0.013) in the metformin cohort. OS was numerically increased in nearly all stages exposed to metformin, though this did not reach statistical significance. The incidence of brain metastases was significantly lower in the metformin cohort (8.9% vs 14.6%, p=0.039).Conclusion: This is the first study to demonstrate significantly improved clinical outcomes in diabetic melanoma patients exposed to metformin. Overall, these results provide further rationale for ongoing clinical trials studying the potential augmentation of checkpoint blockade with metformin in advanced melanoma.
View details for DOI 10.3389/fonc.2023.1075823
View details for PubMedID 37397389
Tumor-Infiltrating Lymphocyte Therapy in Melanoma: Facts to the Future.
Clinical cancer research : an official journal of the American Association for Cancer Research
Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) is gaining momentum and demonstrating durable responses in patients with advanced melanoma. Although increasingly considered as a treatment option for select patients with melanoma, TIL therapy is not yet approved by any regulatory agency. Pioneering studies with first-generation TIL therapy, undertaken before the advent of modern melanoma therapeutics, demonstrated clinical efficacy and remarkable long-term overall survival, reaching beyond 20 months for responding patients. TIL therapy is a multi-step process of harvesting patient-specific tumor-resident T cells from tumors, ex vivo T-cell expansion, and re-infusion into the same patient after a lymphodepleting preparative regimen, with subsequent supportive interleukin-2 administration. Objective response rates between 30% and 50% have consistently been observed in heavily pretreated metastatic melanoma patients, including those who have progressed after modern immune checkpoint inhibitors and BRAF targeted agents, a population with high unmet medical need. Although significant strides have been made in modern TIL therapeutics, refinement strategies to optimize patient selection, enhance TIL production, and improve efficacy are being explored. Here, we review past and present experience, current challenges, practical considerations, and future aspirations in the evolution of TIL therapy for the treatment of melanoma as well as other solid tumors.
View details for DOI 10.1158/1078-0432.CCR-22-1922
View details for PubMedID 36485001
Case report: Later onset of NRAS-mutant metastatic melanoma in a patient with a partially-excised giant congenital melanocytic nevus.
Frontiers in medicine
2022; 9: 1086473
Despite recent advances in treatment and surveillance, metastatic melanoma still carries a poor prognosis. Large/giant congenital melanocytic nevi (CMNs) constitute a known risk factor for the condition, with the greatest risk for malignant transformation thought to be during childhood (median age at diagnosis of 3 years in a previous cohort). Herein, we present the case of a 30-year-old male who, after undergoing multiple excision/grafting procedures for a giant CMN as a child, was diagnosed with an NRAS-mutant, MDM2-amplified metastatic melanoma more than 20 years later. Response to ipilimumab/nivolumab immunotherapy, cisplatin/vinblastine/temozolomide chemotherapy, and nivolumab/relatlimab immunotherapy was poor. This case highlights the importance of lifetime monitoring with once-yearly dermatological examination (including lymph node palpation) in large/giant CMN patients, as well as the need for further clinical trials evaluating novel therapies for NRAS-mutant melanoma.
View details for DOI 10.3389/fmed.2022.1086473
View details for PubMedID 36569151
View details for PubMedCentralID PMC9773131
Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2022; 40 (33): 3858-3867
Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT.We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs).Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs (P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months).Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.
View details for DOI 10.1200/JCO.22.01148
View details for PubMedID 35802849
View details for PubMedCentralID PMC9671756
Neoadjuvant relatlimab and nivolumab in resectable melanoma.
2022; 611 (7934): 155-160
Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.
View details for DOI 10.1038/s41586-022-05368-8
View details for PubMedID 36289334
View details for PubMedCentralID PMC9607737
- Inflammatory vulvar dermatoses following immune checkpoint inhibitor therapy. American journal of obstetrics and gynecology 2022
Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.
The British journal of dermatology
2022; 187 (3): 401-410
Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African.To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups.Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal.In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes.Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.
View details for DOI 10.1111/bjd.21241
View details for PubMedID 35293617
The "Great Debate" at Melanoma Bridge 2021, December 2nd-4th, 2021.
Journal of translational medicine
2022; 20 (1): 200
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
View details for DOI 10.1186/s12967-022-03406-7
View details for PubMedID 35538491
View details for PubMedCentralID PMC9087170
Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2022; 40 (10): 1059-1067
Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear.The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety.Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity.The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi.
View details for DOI 10.1200/JCO.21.01570
View details for PubMedID 34928709
View details for PubMedCentralID PMC8966970
Adoptive Cell Transfer and Vaccines in Melanoma: The Horizon Comes Into View.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2022; 42: 1-8
Over the past four decades, cancer immunotherapy for melanoma has evolved from single-agent, type-I cytokine therapy to combination immune checkpoint inhibition. Along the way, breakthroughs in the fields of cell therapy and cancer vaccination have been made as well. The early data from adoptive cell therapy, involving the delivery of tumor infiltrating lymphocytes harvested from resected tumors, was generated at the National Cancer Institute. Subsequently, a limited number of centers across the globe have developed programs to deliver these therapies. Recently, more widespread availability of this therapy has been made possible by centralizing the growth and expansion of tumor infiltrating lymphocyte products, then distributing the products for delivery of therapy at numerous academic medical centers. Work is ongoing to optimize these treatments with additional cell types and/or modified cell products, and to determine the best ways of combining these treatments with immune checkpoint inhibition. Similarly, tumor vaccination strategies are undergoing dramatic changes, transitioning the field from peptide-based vaccines to next-generation sequencing and T-cell receptor sequencing. These changes help improve the selection of targeted antigens by finding more immunogenic options, and they help with the development of lipid nanoparticles and mRNA delivery. In short, evolution of the approaches that are revolutionizing infectious disease vaccination has been ongoing, and there are promising preliminary data in patients with melanoma.
View details for DOI 10.1200/EDBK_351114
View details for PubMedID 35561301
Quantitative cerebrospinal fluid circulating tumor cells are a potential biomarker of response for proton craniospinal irradiation for leptomeningeal metastasis.
2021; 3 (1): vdab181
Leptomeningeal metastasis (LM) involves cerebrospinal fluid (CSF) seeding of tumor cells. Proton craniospinal irradiation (pCSI) is potentially effective for solid tumor LM. We evaluated whether circulating tumor cells (CTCs) in the CSF (CTCCSF), blood (CTCblood), and neuroimaging correlate with outcomes after pCSI for LM.We describe a single-institution consecutive case series of 58 patients treated with pCSI for LM. Pre-pCSI CTCs, the change in CTC post-pCSI (Δ CTC), and MRIs were examined. Central nervous system progression-free survival (CNS-PFS) and overall survival (OS) from pCSI were determined using Kaplan Meier analysis, Cox proportional-hazards regression, time-dependent ROC analysis, and joint modeling of time-varying effects and survival outcomes.The median CNS-PFS and OS were 6 months (IQR: 4-9) and 8 months (IQR: 5-13), respectively. Pre-pCSI CTCCSF < 53/3mL was associated with improved CNS-PFS (12.0 vs 6.0 months, P < .01). Parenchymal brain metastases (n = 34, 59%) on pre-pCSI MRI showed worse OS (7.0 vs 13 months, P = .01). Through joint modeling, CTCCSF was significantly prognostic of CNS-PFS (P < .01) and OS (P < .01). A Δ CTC-CSF≥37 cells/3mL, the median Δ CTC-CSF at nadir, showed improved CNS-PFS (8.0 vs 5.0 months, P = .02) and further stratified patients into favorable and unfavorable subgroups (CNS-PFS 8.0 vs 4.0 months, P < .01). No associations with CTCblood were found.We found the best survival observed in patients with low pre-pCSI CTCCSF and intermediate outcomes for patients with high pre-pCSI CTCCSF but large Δ CTC-CSF. These results favor additional studies incorporating pCSI and CTCCSF measurement earlier in the LM treatment paradigm.
View details for DOI 10.1093/noajnl/vdab181
View details for PubMedID 34993483
View details for PubMedCentralID PMC8717892
Dermatologic infections in cancer patients treated with checkpoint inhibitors.
Journal of the American Academy of Dermatology
2021; 85 (6): 1528-1536
The incidence of dermatologic infections in patients receiving checkpoint inhibitors (CPIs) has not been systematically described.Identify the incidence of dermatologic infections in patients who received CPIs.Retrospective review of dermatologic infections in patients who received CPIs between 2005 and 2020 and were evaluated by dermatologists at Memorial Sloan Kettering Cancer Center.Of 2061 patients in the study, 1292 were actively receiving CPIs (≤ 90 days since the last dose) and 769 had previously been on CPIs (> 90 days since the last dose). The dermatologic infection rate was significantly higher in patients with active CPI treatment (17.5%) than in patients not actively being treated (8.2%; P < .0001). In patients on CPIs, 82 (36.2%), 78 (34.5%), and 48 (21.2%) had bacterial, fungal, and viral infections, respectively, and 18 (8.0%) had polymicrobial infections. Anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy was associated with the highest risk of infection (hazard ratio, 2.93; 95% confidence interval, 1.87 to 4.60; P < .001).Retrospective design and sample limited to patients referred to dermatology.Patients actively receiving CPIs are more susceptible to dermatologic infections, with anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy carrying the highest risk, suggesting that the index of suspicion for infections should be increased in these patients to minimize morbidity and optimize care.
View details for DOI 10.1016/j.jaad.2021.03.039
View details for PubMedID 33744355
View details for PubMedCentralID PMC8446092
Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy.
Clinical cancer research : an official journal of the American Association for Cancer Research
2021; 27 (21): 5993-6000
Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.
View details for DOI 10.1158/1078-0432.CCR-21-1283
View details for PubMedID 34376536
View details for PubMedCentralID PMC9401488
Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.
2021; 6 (20)
Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8+ T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8+ T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.
View details for DOI 10.1172/jci.insight.151035
View details for PubMedID 34676831
View details for PubMedCentralID PMC8564916
Risks and benefits of reinduction ipilimumab/nivolumab in melanoma patients previously treated with ipilimumab/nivolumab.
Journal for immunotherapy of cancer
2021; 9 (10)
In melanoma patients who progress after prior ipilimumab/nivolumab (ipi/nivo) combination immunotherapy, there is no information regarding the risks and benefits of reinduction ipi/nivo.This was a retrospective review of 26 melanoma patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2012 who received reinduction ipi/nivo at least 6 months following completion of an initial course of ipi/nivo. We collected data on demographics, genetics, immune-related adverse events (irAEs), best overall responses (BORs), time to treatment failure (TTF) and overall survival (OS).The BOR rate (complete response+partial response) was 74% (95% CI 52% to 90%) after the first course of ipi/nivo but only 23% (95% CI 8% to 45%)) after reinduction. Response to reinduction did not correlate with response to the initial course. Among the 16 patients who had an objective response to the first course, only four (25%) responded to reinduction. Of five patients who did not respond to the first course, one responded to reinduction. For all patients, median TTF was 5.3 months after reinduction; TTF was shorter for reinduction than for the first course in 85% of patients. Median OS from reinduction was 8.4 months; estimated 2-year OS was 18%. Although reinduction was associated with fewer irAEs than the initial course of ipi/nivo (58% of patients vs 85% of patients in the initial course), eight (31%) patients experienced at least one new irAE after the second course.BOR rate and TTF were markedly less favorable after reinduction with ipi/nivo than after the initial course of ipi/nivo. Reinduction ipi/nivo was associated with frequent irAEs although less frequent than for the initial course.
View details for DOI 10.1136/jitc-2021-003395
View details for PubMedID 34702752
View details for PubMedCentralID PMC8549669
Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy.
Journal for immunotherapy of cancer
2021; 9 (10)
Immune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis.In this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We also assessed progression-free survival (PFS) and overall survival.Of 76 patients studied (50 (66%) male; median age 67 years; 62 (82%) with melanoma, 5 (7%) with lung cancer, 2 (3%) with head and neck cancer, and 7 (9%) with other cancers; median follow-up 25.1 months (range=0.2-99 months)), 51 (67%) received anti-PD-1 antibodies, 8 (11%) anti-CTLA-4, and 17 (22%) combination of anti-PD-1/CTLA-4. All patients had pre-existing psoriasis, most frequently plaque psoriasis (46 patients (61%)) and 15 (20%) with psoriatic arthritis. Forty-one patients (54%) had received any prior therapy for psoriasis although only two (3%) were on systemic immunosuppression at ICI initiation. With ICI treatment, 43 patients (57%) experienced a psoriasis flare of cutaneous and/or extracutaneous disease after a median of 44 days of receiving ICI. Of those who experienced a flare, 23 patients (53%) were managed with topical therapy only; 16 (21%) needed systemic therapy. Only five patients (7%) required immunotherapy discontinuation for psoriasis flare. Forty-five patients (59%) experienced other irAEs, 17 (22%) of which were grade 3/4. PFS with landmark analysis was significantly longer in patients with a psoriasis flare versus those without (39 vs 8.7 months, p=0.049).In this multicenter study, ICI therapy was associated with frequent psoriasis exacerbation, although flares were manageable with standard psoriasis treatments and few required ICI discontinuation. Patients who experienced disease exacerbation performed at least as well as those who did not. Thus, pre-existing psoriasis should not prevent patients from receiving ICIs for treatment of malignancy.
View details for DOI 10.1136/jitc-2021-003066
View details for PubMedID 34635495
View details for PubMedCentralID PMC8506877
LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade.
Science translational medicine
2021; 13 (608)
Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3+CD8+ T cell population. Patients with melanoma with a LAG+ immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG- immunotype (P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG+ immunotype was significantly associated with response (P = 0.007), survival (P < 0.001), and progression-free survival (P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG+ immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG+ immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.
View details for DOI 10.1126/scitranslmed.abf5107
View details for PubMedID 34433638
View details for PubMedCentralID PMC9254663
- Ipilimumab versus ipilimumab plus anti-PD-1 for metastatic melanoma reply LANCET ONCOLOGY 2021; 22 (8): E343-E344
Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.
Journal for immunotherapy of cancer
2021; 9 (7)
Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
View details for DOI 10.1136/jitc-2021-002890
View details for PubMedID 34281989
View details for PubMedCentralID PMC8291304
Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
The Lancet. Oncology
2021; 22 (6): 836-847
Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.None.
View details for DOI 10.1016/S1470-2045(21)00097-8
View details for PubMedID 33989557
Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas.
Clinical cancer research : an official journal of the American Association for Cancer Research
2021; 27 (8): 2226-2235
Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months.Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.
View details for DOI 10.1158/1078-0432.CCR-20-4189
View details for PubMedID 33509808
View details for PubMedCentralID PMC8046739
Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade.
Journal for immunotherapy of cancer
2021; 9 (2)
Pneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.We performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.From 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3-4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.Steroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.
View details for DOI 10.1136/jitc-2020-001884
View details for PubMedID 33568350
View details for PubMedCentralID PMC7878154
Factors Determining Long-Term Antitumor Responses to Immune Checkpoint Blockade Therapy in Melanoma.
Frontiers in immunology
2021; 12: 810388
With the increasing promise of long-term survival with immune checkpoint blockade (ICB) therapies, particularly for patients with advanced melanoma, clinicians and investigators are driven to identify prognostic and predictive factors that may help to identify individuals who are likely to experience durable benefit. Several ICB combinations are being actively developed to expand the armamentarium of treatments for patients who may not achieve long-term responses to ICB single therapies alone. Thus, negative predictive markers are also of great interest. This review seeks to deepen our understanding of the mechanisms underlying the durability of ICB treatments. We will discuss the currently available long-term data from the ICB clinical trials and real-world studies describing the survivorship of ICB-treated melanoma patients. Additionally, we explore the current treatment outcomes in patients rechallenged with ICB and the patterns of ICB resistance based on sites of disease, namely, liver or CNS metastases. Lastly, we discuss the landscape in melanoma in the context of prognostic or predictive factors as markers of long-term response to ICB.
View details for DOI 10.3389/fimmu.2021.810388
View details for PubMedID 35087529
View details for PubMedCentralID PMC8787112
The future of cancer immunotherapy: microenvironment-targeting combinations.
2020; 30 (6): 507-519
Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.
View details for DOI 10.1038/s41422-020-0337-2
View details for PubMedID 32467593
View details for PubMedCentralID PMC7264181
Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2020; 38 (15): 1655-1663
To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients.We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death.CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab.In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.
View details for DOI 10.1200/JCO.19.01464
View details for PubMedID 32053428
View details for PubMedCentralID PMC7238490
- Another Victory for Immune Checkpoint Blockade in Melanoma: Adjuvant Ipilimumab Over Interferon JOURNAL OF CLINICAL ONCOLOGY 2020; 38 (6): 529-+
Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids.
The Journal of experimental medicine
2019; 216 (12): 2701-2713
Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8+ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8+ T cell proliferation. Secondary challenge using tumors with/without the neoantigen showed selective progression in tumors lacking the neoantigen when corticosteroids were administered. Corticosteroids decreased low- but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells. In a small cohort of human melanoma patients, overall survival was shorter after treatment with CTLA-4 blockade in patients who received early corticosteroids or had low tumor mutation burden. Together, low-affinity memory T cells are dominantly suppressed by corticosteroids, necessitating careful and thoughtful corticosteroid use.
View details for DOI 10.1084/jem.20190738
View details for PubMedID 31537643
View details for PubMedCentralID PMC6888983
Modifiable Host Factors in Melanoma: Emerging Evidence for Obesity, Diet, Exercise, and the Microbiome.
Current oncology reports
2019; 21 (8): 72
We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies. Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.
View details for DOI 10.1007/s11912-019-0814-2
View details for PubMedID 31263961
View details for PubMedCentralID PMC7472428
Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?
2019; 79 (10): 2447-2456
The immune system plays an important role in controlling cancer growth. However, cancers evolve to evade immune detection. Immune tolerance and active immune suppression results in unchecked cancer growth and progression. A major contributor to immune tolerance is the tumor physiologic microenvironment, which includes hypoxia, hypoglucosis, lactosis, and reduced pH. Preclinical and human studies suggest that exercise elicits mobilization of leukocytes into circulation (also known as "exercise-induced leukocytosis"), especially cytotoxic T cells and natural killer cells. However, the tumor physiologic microenvironment presents a significant barrier for these cells to enter the tumor and, once there, properly function. We hypothesize that the effect of exercise on the immune system's ability to control cancer growth is linked to how exercise affects the tumor physiologic microenvironment. Normalization of the microenvironment by exercise may promote more efficient innate and adaptive immunity within the tumor. This review summarizes the current literature supporting this hypothesis.
View details for DOI 10.1158/0008-5472.CAN-18-2468
View details for PubMedID 31068341
View details for PubMedCentralID PMC7474542
Exercise as Adjunct Therapy in Cancer
SEMINARS IN RADIATION ONCOLOGY
2019; 29 (1): 16-24
Data from observational studies indicate that both physical activity as well as exercise (ie, structured physical activity) is associated with reductions in the risk of recurrence and cancer mortality after a diagnosis of certain forms of cancer. Emerging evidence from preclinical studies indicates that physical activity/exercise paradigms regulate intratumoral vascular maturity and perfusion, hypoxia, and metabolism and augments the antitumor immune response. Such responses may, in turn, enhance response to standard anticancer treatments. For instance, exercise improves efficacy of chemotherapeutic agents, and there is rationale to believe that it will also improve radiotherapy response. This review overviews the current preclinical as well as clinical evidence supporting exercise modulation of therapeutic response and postulated biological mechanisms underpinning such effects. We also examine the implications for tumor response to radiation, chemotherapy, and immunotherapy.
View details for DOI 10.1016/j.semradonc.2018.10.001
View details for Web of Science ID 000454569500003
View details for PubMedID 30573180
View details for PubMedCentralID PMC6656408
Bigger Is Not Always Better: Tumor Size and Prognosis in Advanced Melanoma
CLINICAL CANCER RESEARCH
2018; 24 (20): 4915-4917
Tumor burden is a key consideration for the treatment of solid malignancies. Large baseline tumor size (an assessment of volume of disease in target lesions prior to treatment), elevated lactate dehydrogenase (LDH), and site of disease are prognostic of poor overall survival (OS) for patients with advanced melanoma treated with pembrolizumab. Clin Cancer Res; 24(20); 4915-7. ©2018 AACR See related article by Joseph et al., p. 4960.
View details for DOI 10.1158/1078-0432.CCR-18-1311
View details for Web of Science ID 000447598900001
View details for PubMedID 29903895
Combination Controversies: Checkpoint Inhibition Alone or in Combination for the Treatment of Melanoma?
Oncology (Williston Park, N.Y.)
2018; 32 (5): 228-34
The immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have dramatically improved outcomes for patients with metastatic melanoma; however, not all patients benefit from monotherapy with these agents. To address this issue, complementary combinations of immunotherapy are increasingly being explored as a strategy to improve outcomes. However, combinatorial approaches come with heightened risk of toxicity. In this review, we highlight combinations for which there are prospective data from clinical trials. The combinations discussed include ipilimumab plus anti-programmed death 1 agents, ipilimumab plus granulocyte-macrophage colony-stimulating factor, checkpoint inhibitor plus talimogene laherparepvec, ipilimumab plus chemotherapy, checkpoint inhibitor plus BRAF/MEK targeted therapy, and checkpoint inhibition plus radiation therapy. We discuss data regarding the efficacy and toxicity of combination therapy, and we identify clinical scenarios that may favor treatment with combination therapy.
View details for PubMedID 29847853
- The brim of uncertainty in adjuvant treatment of melanoma LANCET ONCOLOGY 2018; 19 (4): 436-437
Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma.
2018; 7 (3): 690-697
Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan-Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to-lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD-1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD-1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD-1 alone.
View details for DOI 10.1002/cam4.1356
View details for PubMedID 29468834
View details for PubMedCentralID PMC5852343
Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.
Annals of oncology : official journal of the European Society for Medical Oncology
2018; 29 (1): 250-255
Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.
View details for DOI 10.1093/annonc/mdx642
View details for PubMedID 29045547
View details for PubMedCentralID PMC5834131
- End-of-Life Care for Patients with Potentially Resectable Pancreatic Cancer Who Received Radiation Therapy ELSEVIER SCIENCE INC. 2017: E529-E530
Impact of Age on Outcomes with Immunotherapy for Patients with Melanoma.
2017; 22 (8): 963-971
Monoclonal antibodies (mAb) targeting PD-1/PD-L1 have revolutionized melanoma treatment, yet data regarding effectiveness and tolerability across age groups is limited. We sought to determine the impact of age on overall survival (OS), progression-free survival (PFS), and rates of immune-mediated toxicities in patients treated with anti-PD-1/anti-PD-L1 mAb at two academic medical centers.We retrospectively collected data on all patients with metastatic melanoma treated with anti-PD-1/PD-L1 mAb between May 2009 and April 2015. We used Kaplan-Meier and Cox regression analyses to assess OS and PFS and identify factors associated with these outcomes. We also compared rates of autoimmune toxicity across age groups.Of 254 patients, 57 (22.4%) were <50 years old, 85 (33.5%) were age 50-64, 65 (25.6%) were age 65-74, and 47 (18.5%) were ≥75 years. Across age groups, no differences existed in median OS (age <50: 22.9 months, age 50-64: 25.3 months, age 65-74: 22.0 months, age ≥75: 24.3 months) or PFS (age <50: 4.1 months, age 50-64: 6.5 months, age 65-74: 5.4 months, age ≥75: 7.9 months). The presence of liver metastases and elevated pre-treatment lactate dehydrogenase (LDH) were associated with reduced OS. Presence of liver metastasis, pretreatment LDH, BRAF mutation, and type of melanoma correlated with PFS. Overall, 110 patients (43.3%) experienced immune-mediated toxicities; 25 (9.8%) had colitis and 26 (10.2%) had endocrine toxicity. Rates of colitis, hepatitis, and pneumonitis did not differ across age groups.We demonstrated that patients could safely tolerate anti-PD1/PDL-1 mAb therapy and achieve similar outcomes regardless of their age.Immunotherapy has revolutionized treatment for patients with metastatic melanoma, yet data are lacking regarding the effectiveness and tolerability of these treatments for older patients. In this study, we demonstrated that patients with melanoma safely tolerate immunotherapy and achieve similar outcomes regardless of their age. Specifically, we utilized data from two academic cancer centers and found no significant difference in overall survival, progression free survival, or immune-related toxicities, other than arthritis, across age groups. As the population ages, studies such as this will become critical to help us understand how best to treat older adults with cancer.
View details for DOI 10.1634/theoncologist.2016-0450
View details for PubMedID 28476944
View details for PubMedCentralID PMC5553960
Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data
2016; 76 (14): 4032-4050
A major objective of the emerging field of exercise-oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression, and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of several forms of cancer; similarly, emerging data suggest that exercise exposure after a cancer diagnosis may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies to validate the biological efficacy of exercise, identify the optimal "dose", and pinpoint mechanisms of action. To evaluate the current evidence base, we conducted a critical systematic review of in vivo studies investigating the effects of exercise in cancer prevention and progression. Studies were evaluated on the basis of tumor outcomes (e.g., incidence, growth, latency, metastasis), dose-response, and mechanisms of action, when available. A total of 53 studies were identified and evaluated on tumor incidence (n = 24), tumor growth (n = 33), or metastasis (n = 10). We report that the current evidence base is plagued by considerable methodologic heterogeneity in all aspects of study design, endpoints, and efficacy. Such heterogeneity precludes meaningful comparisons and conclusions at present. To this end, we provide a framework of methodologic and data reporting standards to strengthen the field to guide the conduct of high-quality studies required to inform translational, mechanism-driven clinical trials. Cancer Res; 76(14); 4032-50. ©2016 AACR.
View details for DOI 10.1158/0008-5472.CAN-16-0887
View details for Web of Science ID 000381111400003
View details for PubMedID 27381680
View details for PubMedCentralID PMC5378389
Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.
Journal of the National Cancer Institute
2015; 107 (5)
Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.
View details for DOI 10.1093/jnci/djv040
View details for PubMedID 25780062
View details for PubMedCentralID PMC4822524
Effects and potential mechanisms of exercise training on cancer progression: A translational perspective
BRAIN BEHAVIOR AND IMMUNITY
2013; 30: S75-S87
Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of 'exercise - oncology' has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed.
View details for DOI 10.1016/j.bbi.2012.05.001
View details for Web of Science ID 000316510800010
View details for PubMedID 22610066
View details for PubMedCentralID PMC3638811
Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.
Journal of applied physiology (Bethesda, Md. : 1985)
2012; 113 (2): 263-72
The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.
View details for DOI 10.1152/japplphysiol.01575.2011
View details for PubMedID 22604887
View details for PubMedCentralID PMC3404704
Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.
British journal of cancer
2012; 106 (5): 916-22
In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin.We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification.Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio.We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.
View details for DOI 10.1038/bjc.2012.32
View details for PubMedID 22333602
View details for PubMedCentralID PMC3305967
Effect of pazopanib on tumor microenvironment and liposome delivery.
Molecular cancer therapeutics
2010; 9 (6): 1798-808
Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently "normalize" the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non-small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor "normalization" may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows.
View details for DOI 10.1158/1535-7163.MCT-09-0856
View details for PubMedID 20515941
View details for PubMedCentralID PMC2909540
A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
2010; 26 (5): 514-21
The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia.Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy.Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%).Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.
View details for DOI 10.3109/02656731003639364
View details for PubMedID 20377362
View details for PubMedCentralID PMC2956498