Sunil Arani Reddy

All Publications

• Toward the Development of Functional Biomarker Assays: Analysis of Neoadjuvant Intralesional Oncolytic Virus Response in High-Risk Stage II Melanoma Kirane, A., Lee, D., Ahmad, M., Sharma, S., Serasanambati, M., Lowe, M., Applebee, C., Safrygina, E., Swetter, S., Reddy, S., Warner, A., Funchain, P., Wang, J., Levy, R., Larijani, B., Maverakis, E. SPRINGER. 2024: S33-S34

  View details for Web of Science ID 001185577500066

• ESC Cardio-Oncology Guidelines: A Triumph-But Are We Overscreening? JACC. CardioOncology Witteles, R. M., Reddy, S. A. 2023; 5 (1): 133-136

  View details for DOI 10.1016/j.jaccao.2022.10.008

  View details for PubMedID 36875904

• Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. Cureus Hui, C., Wu, Y. F., Liu, K., Sandhu, N., Blomain, E., Binkley, M. S., Gephart, M. H., Chang, S. D., Li, G. H., Reddy, S. A., Soltys, S. G., Pollom, E. 2022; 14 (11): e31838

  Abstract

  Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

  View details for DOI 10.7759/cureus.31838

  View details for PubMedID 36579260

  View details for PubMedCentralID PMC9788920

• Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020. The oncologist Qian, M. F., Betancourt, N. J., Pineda, A., Maloney, N. J., Nguyen, K. A., Reddy, S. A., Hall, E. T., Swetter, S. M., Zaba, L. C. 2022

  Abstract

  BACKGROUND: Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020.PATIENTS AND METHODS: Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference.RESULTS: Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: beta = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: beta = $3810, 95%CI $365-$7260; pembrolizumab: beta = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days.CONCLUSIONS: Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

  View details for DOI 10.1093/oncolo/oyac219

  View details for PubMedID 36302223

• Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis. Circulation Zhu, H., Galdos, F. X., Lee, D., Waliany, S., Vivian Huang, Y., Ryan, J., Dang, K., Neal, J. W., Wakelee, H. A., Reddy, S. A., Srinivas, S., Lin, L. L., Witteles, R. M., Maecker, H. T., Davis, M. M., Nguyen, P. K., Wu, S. M. 2022: 101161CIRCULATIONAHA121056730

  Abstract

  Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown.To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis.Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls.Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

  View details for DOI 10.1161/CIRCULATIONAHA.121.056730

  View details for PubMedID 35762356

• FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A). Zager, J. S., Orloff, M. M., Ferrucci, P., Glazer, E., Ejaz, A., Richtig, E., Ochsenreither, S., Lowe, M. C., Reddy, S. A., Beasley, G., Gesierich, A., Dummer, R., Arance, A., Fenwick, S., Wheater, M., Ottensmeier, C. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680302329

• Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Thompson, J. A., Schneider, B. J., Brahmer, J., Achufusi, A., Armand, P., Berkenstock, M. K., Bhatia, S., Budde, L. E., Chokshi, S., Davies, M., Elshoury, A., Gesthalter, Y., Hegde, A., Jain, M., Kaffenberger, B. H., Lechner, M. G., Li, T., Marr, A., McGettigan, S., McPherson, J., Medina, T., Mohindra, N. A., Olszanski, A. J., Oluwole, O., Patel, S. P., Patil, P., Reddy, S., Ryder, M., Santomasso, B., Shofer, S., Sosman, J. A., Wang, Y., Zaha, V. G., Lyons, M., Dwyer, M., Hang, L. 2022; 20 (4): 387-405

  Abstract

  The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

  View details for DOI 10.6004/jnccn.2022.0020

  View details for PubMedID 35390769

• The complexity of carcinosarcoma. Oncology (Williston Park, N.Y.) Reddy, S. 1800; 35 (12): 814

  View details for DOI 10.46883/2021.25920934

  View details for PubMedID 35088999

• Intracranial Response to Combination BRAF and MEK Inhibitor Therapy in Patients with Metastatic Melanoma Hui, C., Wu, Y., Liu, K., Sandhu, N., Blomain, E., Binkley, M., Gephart, M., Chang, S., Li, G., Reddy, S., Gibbs, I., Soltys, S., Pollom, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S48-S49

  View details for Web of Science ID 000701779700077

• Use of a computer model and care coaches to increase advance care planning conversations for patients with metastatic cancer Gupta, D., Fardeen, T., Teuteberg, W., Seevaratnam, B., Asuncion, M., Alves, N., Rogers, B., Neal, J. W., Fan, A. C., Parikh, D., Patel, M. I., Shah, S., Srinivas, S., Huang, J. E., Reddy, S. A., Ganjoo, K. N., Bui, N., Hansen, J., Gensheimer, M. F., Ramchandran, K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2020.39.28_suppl.8

  View details for Web of Science ID 000707130200008

• Complete remission from intralesional talimogene laherparepvec for regionally advanced Merkel cell carcinoma in an immunocompromised solid organ transplant patient. JAAD case reports Hirotsu, K. E., Hua, V., Tran, A. T., Morris, L., Reddy, S. A., Kwong, B. Y., Zaba, L. C. 2021; 13: 144-146

  View details for DOI 10.1016/j.jdcr.2021.05.005

  View details for PubMedID 34195326

• Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases: Preliminary results of FOCUS (PHP-OCM-301/301A) phase III trial. Zager, J. S., Orloff, M., Ferrucci, P., Glazer, E., Ejaz, A., Richtig, E., Ochsenreither, S., Lowe, M. C., Reddy, S. A., Beasley, G., Gesierich, A., Dummer, R., Arance, A., Fenwick, S., Wheater, M., Ottensmeier, C. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.9510

  View details for Web of Science ID 000708120605114

• Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. Journal for immunotherapy of cancer Nghiem, P., Bhatia, S., Lipson, E. J., Sharfman, W. H., Kudchadkar, R. R., Brohl, A. S., Friedlander, P. A., Daud, A., Kluger, H. M., Reddy, S. A., Boulmay, B. C., Riker, A., Burgess, M. A., Hanks, B. A., Olencki, T., Kendra, K., Church, C., Akaike, T., Ramchurren, N., Shinohara, M. M., Salim, B., Taube, J. M., Jensen, E., Kalabis, M., Fling, S. P., Homet Moreno, B., Sharon, E., Cheever, M. A., Topalian, S. L. 2021; 9 (4)

  Abstract

  BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.METHODS: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.RESULTS: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95%CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95%CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.CONCLUSIONS: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.TRIAL REGISTRATION NUMBER: NCT02267603.

  View details for DOI 10.1136/jitc-2021-002478

  View details for PubMedID 33879601

• Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC. CardioOncology Waliany, S., Neal, J. W., Reddy, S., Wakelee, H., Shah, S. A., Srinivas, S., Padda, S. K., Fan, A. C., Colevas, A. D., Wu, S. M., Witteles, R. M., Zhu, H. 2021; 3 (1): 137–39

  View details for DOI 10.1016/j.jaccao.2021.01.004

  View details for PubMedID 33796869

• Liquid biopsy proteomics of uveal melanoma reveals biomarkers associated with metastatic risk. Molecular cancer Velez, G., Nguyen, H. V., Chemudupati, T., Ludwig, C. A., Toral, M., Reddy, S., Mruthyunjaya, P., Mahajan, V. B. 2021; 20 (1): 39

  View details for DOI 10.1186/s12943-021-01336-4

  View details for PubMedID 33627107

• Prognostic value of bone marrow metabolism on pretreatment 18F-FDG PET/CT in patients with metastatic melanoma treated with anti-PD-1 therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Nakamoto, R., Zaba, L. C., Liang, T., Reddy, S. A., Davidzon, G., Aparici, C. M., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. L. 2021

  Abstract

  Purpose: To investigate the prognostic value of 18F-FDG PET/CT parameters in melanoma patients before beginning anti-PD-1 therapy. Methods: Imaging parameters including SUVmax, metabolic tumor volume (MTV), and bone marrow to liver SUVmean ratio (BLR) were measured from baseline PET/CT in 92 patients before the start of anti-PD-1 therapy. Association with survival and imaging parameters combined with clinical factors was evaluated. Clinical and laboratory data between high (> median) and low (≤ median) BLR groups were compared. Results: Multivariate analyses demonstrated that BLR was an independent prognostic factor for PFS and OS (P = 0.017, P = 0.011, respectively). The high BLR group had higher levels of white blood cell count/neutrophil count and C-Reactive Protein than the low BLR group (P < 0.05). Conclusion: Patients with high BLR were associated with poor PFS and OS, potentially explained by evidence of systemic inflammation known to be associated with immunosuppression.

  View details for DOI 10.2967/jnumed.120.254482

  View details for PubMedID 33547210

• Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Zhu, H., Lee, D., Sarah, W., Galdos, F. X., D'Addabbo, J., Fowler, M. B., Reddy, S., Heather, W., Neal, J. W., Witteles, R., Maecker, H. T., Davis, M., Nguyen, P. K., Wu, S. M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.350

  View details for Web of Science ID 000606541500116

• Imaging characteristics and diagnostic performance of F-18-FDG PET/CT for melanoma patients who demonstrate hyperprogressive disease when treated with immunotherapy Nakamoto, R., Zaba, L., Rosenberg, J., Reddy, S., Nobashi, T., Davidzon, G., Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500424

• Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy Nakamoto, R., Zaba, L., Rosenberg, J., Reddy, S., Nobashi, T., Davidzon, G., Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500428

• A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research Postow, M. A., Knox, S. J., Goldman, D. A., Elhanati, Y., Mavinkurve, V., Wong, P., Halpenny, D. F., Reddy, S. A., Vado, K. P., McCabe, D., Ramirez, K. A., Macri, M., Schwarzenberger, P., Ricciardi, T., Ryan, A., Venhaus, R. R., Momtaz, P., Shoushtari, A. N., Callahan, M. K., Chapman, P. B., Wolchok, J. D., Subrahmanyam, P. B., Maecker, H. T., Panageas, K. S., Barker, C. A. 2020

  Abstract

  PURPOSE: Preclinical data suggests radiotherapy is beneficial in combination with immune checkpoint blockade. Clinical trials have explored radiotherapy with single agent immune checkpoint blockade, but no trials have reported radiotherapy with the combination of nivolumab and ipilimumab.EXPERIMENTAL DESIGN: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of radiotherapy. Patients had at least one melanoma metastasis that would benefit from palliative radiotherapy and one metastasis that would not be irradiated. Nivolumab 1mg/kg + ipilimumab 3mg/kg and extracranial radiotherapy with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety.RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment related grade 3-4 adverse events in Cohort A and Cohort B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to radiation. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T cell receptor diversity in some responding patients.CONCLUSIONS: Radiotherapy with nivolumab and ipilimumab was safe compared to historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.

  View details for DOI 10.1158/1078-0432.CCR-19-3936

  View details for PubMedID 32205463

• Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab. Melanoma management Sodji, Q. H., Gutkin, P. M., Swetter, S. M., Reddy, S. A., Hiniker, S. M., Knox, S. J. 2020; 7 (1): MMT36

  Abstract

  Aim: We previously reported a prospective trial evaluating the safety and efficacy of combining ipilimumab and radiation therapy in patients with metastatic melanoma. Herein, we provide a long-term update on patients with complete response (CR) or partial response (PR).Patients & methods: We continued to follow these patients with serial imaging including computed tomography, PET or MRI.Results: Two of the three patients with CR are still alive and without evidence of melanoma but with chronic treatment-induced hypophysitis. The third patient died of hepatocellular carcinoma, but with no evidence of melanoma. Among the three patients with PR, two achieved CR after pembrolizumab monotherapy.Conclusion: This long-term follow up reveals the striking durability of the CRs, which appears to correlate with a grade 2-3 hypophysitis.

  View details for DOI 10.2217/mmt-2019-0020

  View details for PubMedID 32399174

• Economics of alternative dosing strategies for pembrolizumab and nivolumab at a single academic cancer center. Cancer medicine Hall, E., Zhang, J., Kim, E. J., Hwang, G., Chu, G., Bhatia, S., Reddy, S. 2020

  Abstract

  BACKGROUND: The FDA initially approved pembrolizumab and nivolumab for doses based on patient weight, but subsequently amended approval to fixed doses. We estimated savings from novel dosing strategies based on real-world patient data from a single cancer center.METHODS: We analyzed all outpatient doses of pembrolizumab and nivolumab administered at three infusion centers affiliated with our academic hospital between July 1, 2018 and Oct 31, 2018. We estimated savings from several dosing strategies with and without vial sharing between patients.RESULTS: A total of 1029 doses of pembrolizumab or nivolumab were administered for multiple cancer types. For 77% of doses, the weight-based dose was less than the fixed dose. "Dose-minimization" (DM), defined as the lesser of weight-based and fixed dose decreased nivolumab spending by 9% without affecting pembrolizumab spending. DM plus vial sharing decreased pembrolizumab spending by 19% without affecting nivolumab. The differences in savings were due to availability of multiple vial sizes for nivolumab but not pembrolizumab. DM plus vial sharing for both drugs would have saved $1.5 million USD over the 4-month study period.CONCLUSION: New dosing strategies for pembrolizumab and nivolumab can generate large savings without anticipated decrease in efficacy. Barriers include FDA dosing labels, hospital policies against vial sharing, and inaccessibility of smaller vial sizes, which are currently available in other worldwide markets.

  View details for DOI 10.1002/cam4.2888

  View details for PubMedID 31994335

• Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial. The Journal of experimental medicine Frank, M. J., Khodadoust, M. S., Czerwinski, D. K., Haabeth, O. A., Chu, M. P., Miklos, D. B., Advani, R. H., Alizadeh, A. A., Gupta, N. K., Maeda, L. S., Reddy, S. A., Laport, G. G., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Weng, W. K., Sheehan, K. n., Faham, M. n., Okada, A. n., Moore, A. H., Phillips, D. L., Wapnir, I. L., Brody, J. D., Levy, R. n. 2020; 217 (9)

  Abstract

  Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

  View details for DOI 10.1084/jem.20191712

  View details for PubMedID 32558897

• Intracranial Tumor Control Following Immune-Related Adverse Events and Discontinuation of Immunotherapy for Melanoma. World neurosurgery Zhang, M. n., Rodrigues, A. J., Bhambhvani, H. P., Fatemi, P. n., Pollom, E. L., Gibbs, I. C., Thomas, R. P., Soltys, S. G., Hancock, S. L., Chang, S. D., Reddy, S. A., Gephart, M. H., Li, G. n. 2020

  Abstract

  Immunotherapy for melanoma patients with brain metastasis has significantly improved outcomes; however, they have also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports suggest these reactions can precede improved treatment responses. We sought to identify if such association exists for intracranial disease control.We conducted a retrospective chart review of melanoma patients who underwent immunotherapy treatment following diagnosis of brain metastasis. The study cohort was then stratified into two groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analysis were used to evaluate survival and predictors of outcomes.Fifty-two patients met inclusion criteria, seventeen of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 vs 10.5 months (p = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival, mean (33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (p = 0.013, HR = 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (p = 0.015, HR = 10.73) CONCLUSION: Immune related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to demonstrate promising outcomes as a first-line agent for melanoma with brain metastasis.

  View details for DOI 10.1016/j.wneu.2020.08.124

  View details for PubMedID 32853767

• NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. Journal of the National Comprehensive Cancer Network : JNCCN Thompson, J. A., Schneider, B. J., Brahmer, J., Andrews, S., Armand, P., Bhatia, S., Budde, L. E., Costa, L., Davies, M., Dunnington, D., Ernstoff, M. S., Frigault, M., Kaffenberger, B. H., Lunning, M., McGettigan, S., McPherson, J., Mohindra, N. A., Naidoo, J., Olszanski, A. J., Oluwole, O., Patel, S. P., Pennell, N., Reddy, S., Ryder, M., Santomasso, B., Shofer, S., Sosman, J. A., Wang, Y., Weight, R. M., Johnson-Chilla, A., Zuccarino-Catania, G., Engh, A. 2020; 18 (3): 230–41

  Abstract

  The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

  View details for DOI 10.6004/jnccn.2020.0012

  View details for PubMedID 32135517

• Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy. European journal of nuclear medicine and molecular imaging Nakamoto, R. n., Zaba, L. C., Rosenberg, J. n., Reddy, S. A., Nobashi, T. W., Davidzon, G. n., Aparici, C. M., Nguyen, J. n., Moradi, F. n., Iagaru, A. n., Franc, B. L. 2020

  Abstract

  The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs).Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated.The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group.Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

  View details for DOI 10.1007/s00259-020-04792-0

  View details for PubMedID 32296882

• "Giant cell arteritis manifesting as retinal arterial occlusion and paracentral acute middle maculopathy in a patient on pembrolizumab for metastatic uveal melanoma". American journal of ophthalmology case reports Narala, R. n., Reddy, S. A., Mruthyunjaya, P. n. 2020; 20: 100891

  Abstract

  To report the association of pembrolizumab, an immune checkpoint inhibitor (ICI), with giant cell arteritis (GCA) presenting as paracentral acute middle maculopathy (PAMM) secondary to retinal arterial occlusion.86-year old male with history of treated choroidal melanoma now with metastatic uveal melanoma to the liver on pembrolizumab, an ICI, who presented with acute vision loss in the uninvolved left eye. Spectral domain optical coherence tomography showed band-like increased hyperreflectivity in the middle retinal layers at the level of the inner nuclear layer consistent with PAMM. Intravenous fluorescein angiogram demonstrated significant delay in filling of the superotemporal and inferotemporal arteries with nonperfusion of the temporal retina consistent with multiple branch retinal arterial occlusions. Work-up for GCA was performed and temporal artery biopsy showed healed arteritis.Pembrolizumab can cause ocular and life-threatening systemic adverse effects and as use of ICIs has increased, it is important to be aware of these associations. There should be a low threshold for GCA work up in patients on ICI therapy who present with acute vision loss and evidence of retinal occlusive disease with or without classic GCA systemic symptoms.

  View details for DOI 10.1016/j.ajoc.2020.100891

  View details for PubMedID 32913923

  View details for PubMedCentralID PMC7472807

• A phase 1b, open-label, investigator-initiated, proof-of-concept study of pembrolizumab for advanced basal cell carcinomas Chang, A., Duy Tran, Cannon, J., Li, S., Jeng, M., Rieger, K., Reddy, S., Sarin, K., Colevas, D. MOSBY-ELSEVIER. 2019: AB8

  View details for Web of Science ID 000482195000029

• Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy. Amin, A., Milhem, M. M., Long, G. V., Hoimes, C. J., Medina, T., Conry, R., Lao, C. D., Daniels, G. A., Reddy, S. A., Andtbacka, R., Barve, M. A., Shaheen, M. F., Tueting, T., Chisamore, M., Schmidt, E. V., Candia, A., Obiozor, C., Gamelin, E., Janssen, R., Ribas, A. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.9555

  View details for Web of Science ID 000487345806609

• Economic analysis of alternative pembrolizumab and nivolumab dosing strategies at an academic cancer center. Hall, E., Zhang, J., Kim, E., Hwang, G., Bhatia, S., Reddy, S. A. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.6504

  View details for Web of Science ID 000487345806058

• Management of Immunotherapy-Related Toxicities. Version 1.2019 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Thompson, J. A., Schneider, B. J., Brahmer, J., Andrews, S., Armand, P., Bhatia, S., Budde, L. E., Costa, L., Davies, M., Dunnington, D., Ernstoff, M. S., Frigault, M., Hoffner, B., Hoimes, C. J., Lacouture, M., Locke, F., Lunning, M., Mohindra, N. A., Naidoo, J., Olszanski, A. J., Oluwole, O., Patel, S. P., Reddy, S., Ryder, M., Santomasso, B., Shofer, S., Sosman, J. A., Wahidi, M., Wang, Y., Johnson-Chilla, A., Scavone, J. L. 2019; 17 (3): 255–88

  Abstract

  The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

  View details for PubMedID 30865922

• Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Nghiem, P., Bhatia, S., Lipson, E. J., Sharfman, W. H., Kudchadkar, R. R., Brohl, A. S., Friedlander, P. A., Daud, A., Kluger, H. M., Reddy, S. A., Boulmay, B. C., Riker, A. I., Burgess, M. A., Hanks, B. A., Olencki, T., Margolin, K., Lundgren, L. M., Soni, A., Ramchurren, N., Church, C., Park, S. Y., Shinohara, M. M., Salim, B., Taube, J. M., Bird, S. R., Ibrahim, N., Fling, S. P., Homet Moreno, B., Sharon, E., Cheever, M. A., Topalian, S. L. 2019: JCO1801896

  Abstract

  PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited.PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naive to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

  View details for PubMedID 30726175

• Predicting Response to Immunotherapy by Evaluating Tumors, Lymphoid Cell-Rich Organs, and Immune-Related Adverse Events Using FDG-PET/CT. Clinical nuclear medicine Nobashi, T., Baratto, L., Reddy, S. A., Srinivas, S., Toriihara, A., Hatami, N., Yohannan, T. K., Mittra, E. 2019

  Abstract

  PURPOSE: To investigate whether the evaluation of tumors, lymphoid cell-rich organs, and immune-related adverse events (IRAE) with F-FDG PET/CT can predict the efficacy and outcome of immunotherapy.METHODS: Forty patients who underwent F-FDG-PET/CT scans before and after therapy with immune checkpoint inhibitors from December 2013 to December 2016 were retrospectively enrolled (malignant melanoma, n = 21; malignant lymphoma, n = 11; renal cell carcinoma, n = 8). SUVmax of the baseline and first restaging scans were evaluated in tumors, spleen, bone marrow, thyroid and pituitary glands, and were correlated to best overall response in the first year after therapy; IRAE-affected areas were also evaluated.RESULTS: Interval change between the baseline and first restaging scans showed that patients with a clinical benefit had a significant decrease in tumor parameters (P < 0.001). All patients with an increase of SUVmax in the thyroid of more than 1.5 (n = 5) on the first restaging scan had a complete response (CR) in 1 year. Patients with CR within 1 year (n = 22) were significantly associated with a favorable long-term outcome (P = 0.002). Nine patients with IRAE findings had CR at final evaluation. Among IRAE, thyroiditis was seen significantly earlier than arthritis (P = 0.040).CONCLUSIONS: The decrease of tumor parameters at early time-point PET scans was seen in patients with immunotherapy who had clinical benefit within 1 year. PET-detectable IRAE was useful for prediction of a favorable outcome. Early development of thyroiditis may particularly represent an early response indicator to immunotherapy.

  View details for PubMedID 30688730

• Complete Response of Metastatic Melanoma to Local Radiation and Immunotherapy: 6.5 Year Follow-Up. Cureus Gutkin, P. M., Hiniker, S. M., Swetter, S. M., Reddy, S. A., Knox, S. J. 2018; 10 (12): e3723

  Abstract

  The combined use of immunotherapy and radiation therapy is emerging as a potentially effective treatment for patients with immunogenic tumors such as melanoma; however, evidence for long-term treatment outcomes is lacking. Herein, we summarize our previously described case study of a patient with metastatic melanoma treated with two cycles of ipilimumab, followed by stereotactic body radiotherapy to two of seven liver metastases, with two additional cycles of ipilimumab. In the longest follow-up to date, we report a successful treatment outcome at 6.5 years. Our patient remains in complete remission, with no evidence of disease or recurrence 6.5 years after treatment. He continues to manage chronic hypophysitis developed secondary to immunotherapy and has developed osteopenia from prolonged systemic glucocorticoid use. The use of radiotherapy in combination with targeted immune therapy appears to be an effective treatment strategy, with long-lasting efficacy.

  View details for PubMedID 30788205

• Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study. Journal of the American Academy of Dermatology Chang, A. L., Tran, D. C., Cannon, J. G., Li, S. n., Jeng, M. n., Patel, R. n., Van der Bokke, L. n., Pague, A. n., Brotherton, R. n., Rieger, K. E., Satpathy, A. T., Yost, K. E., Reddy, S. n., Sarin, K. n., Colevas, A. D. 2018

  View details for PubMedID 30145186

• Phase I Trial: SABR and Ipilimumab-Letter. Clinical cancer research : an official journal of the American Association for Cancer Research Hiniker, S. M., Reddy, S. A., Swetter, S. M., Knox, S. J. 2017; 23 (1): 320

  View details for PubMedID 28049160

• A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. International journal of radiation oncology, biology, physics Hiniker, S. M., Reddy, S. A., Maecker, H. T., Subrahmanyam, P. B., Rosenberg-Hasson, Y., Swetter, S. M., Saha, S., Shura, L., Knox, S. J. 2016; 96 (3): 578-588

  Abstract

  Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

  View details for DOI 10.1016/j.ijrobp.2016.07.005

  View details for PubMedID 27681753

• Romidepsin for the treatment of relapsed/refractory cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome): Use in a community setting. Critical reviews in oncology/hematology Reddy, S. A. 2016; 106: 99-107

  Abstract

  Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of rare non-Hodgkin lymphomas that arise in the skin. In advanced stages, CTCL becomes systemic and is associated with poor prognosis. Diagnosis of CTCL and treatment of early-stage disease with topical therapies often occurs under the care of a dermatologist. Community oncologists see few patients with CTCL due to direct referrals from dermatologists to academic or lymphoma specialty centers. However, some patients will continue to be managed in a community setting. Currently there is no evidence-based stepwise algorithm for treatment of patients with CTCL, and guidelines suggest a wide range of systemic therapies, including biologics, targeted agents, and more traditional chemotherapies. To provide optimal care in a community setting, oncologists must become familiar with newer nonchemotherapeutic treatment options. This review highlights romidepsin, a histone deacetylase inhibitor approved for the treatment of patients with CTCL who have received ≥1 prior systemic therapy.

  View details for DOI 10.1016/j.critrevonc.2016.07.001

  View details for PubMedID 27637355

• PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma NEW ENGLAND JOURNAL OF MEDICINE Nghiem, P. T., Bhatia, S., Lipson, E. J., Kudchadkar, R. R., Miller, N. J., Annamalai, L., Berry, S., Chartash, E. K., Daud, A., Fling, S. P., Friedlander, P. A., Kluger, H. M., Kohrt, H. E., Lundgren, L., Margolin, K., Mitchell, A., Olencki, T., Pardoll, D. M., Reddy, S. A., Shantha, E. M., Sharfman, W. H., Sharon, E., Shemanski, L. R., Shinohara, M. M., Sunshine, J. C., Taube, J. M., Thompson, J. A., Townson, S. M., Yearley, J. H., Topalian, S. L., Cheever, M. A. 2016; 374 (26): 2542-2552

  Abstract

  Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1.In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).

  View details for DOI 10.1056/NEJMoa1603702

  View details for PubMedID 27093365

• Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases JOURNAL OF NEURO-ONCOLOGY Li, Y., Pan, W., Connolly, I. D., Reddy, S., Nagpal, S., Quake, S., Gephart, M. H. 2016; 128 (1): 93-100

  Abstract

  Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  View details for DOI 10.1007/s11060-016-2081-5

  View details for PubMedID 26961773

• Toward rapid learning in cancer treatment selection: An analytical engine for practice-based clinical data. Journal of biomedical informatics Finlayson, S. G., Levy, M., Reddy, S., Rubin, D. L. 2016; 60: 104-113

  Abstract

  Wide-scale adoption of electronic medical records (EMRs) has created an unprecedented opportunity for the implementation of Rapid Learning Systems (RLSs) that leverage primary clinical data for real-time decision support. In cancer, where large variations among patient features leave gaps in traditional forms of medical evidence, the potential impact of a RLS is particularly promising. We developed the Melanoma Rapid Learning Utility (MRLU), a component of the RLS, providing an analytical engine and user interface that enables physicians to gain clinical insights by rapidly identifying and analyzing cohorts of patients similar to their own.A new approach for clinical decision support in Melanoma was developed and implemented, in which patient-centered cohorts are generated from practice-based evidence and used to power on-the-fly stratified survival analyses. A database to underlie the system was generated from clinical, pharmaceutical, and molecular data from 237 patients with metastatic melanoma from two academic medical centers. The system was assessed in two ways: (1) ability to rediscover known knowledge and (2) potential clinical utility and usability through a user study of 13 practicing oncologists.The MRLU enables physician-driven cohort selection and stratified survival analysis. The system successfully identified several known clinical trends in melanoma, including frequency of BRAF mutations, survival rate of patients with BRAF mutant tumors in response to BRAF inhibitor therapy, and sex-based trends in prevalence and survival. Surveyed physician users expressed great interest in using such on-the-fly evidence systems in practice (mean response from relevant survey questions 4.54/5.0), and generally found the MRLU in particular to be both useful (mean score 4.2/5.0) and useable (4.42/5.0).The MRLU is an RLS analytical engine and user interface for Melanoma treatment planning that presents design principles useful in building RLSs. Further research is necessary to evaluate when and how to best use this functionality within the EMR clinical workflow for guiding clinical decision making.The MRLU is an important component in building a RLS for data driven precision medicine in Melanoma treatment that could be generalized to other clinical disorders.

  View details for DOI 10.1016/j.jbi.2016.01.005

  View details for PubMedID 26836975

  View details for PubMedCentralID PMC4836997

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  Abstract

  In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma LEUKEMIA & LYMPHOMA Kim, E. J., Kim, Y. H., Rook, A. H., Lerner, A., Duvic, M., Reddy, S., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Waksman, J., Whittaker, S. 2015; 56 (10): 2847-2854

  Abstract

  Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.

  View details for DOI 10.3109/10428194.2015.1014360

  View details for Web of Science ID 000365241700015

  View details for PubMedID 25791237

  View details for PubMedCentralID PMC4732431

• Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy. JAMA dermatology Chen, F. W., Tseng, D., Reddy, S., Daud, A. I., Swetter, S. M. 2014; 150 (11): 1209-1212

  Abstract

  Eruptive melanocytic nevi (EMN) are characterized by the sudden onset of numerous melanocytic nevi and have been traditionally described in the setting of immunosuppression. Selective BRAF inhibitors, such as vemurafenib cause multiple cutaneous adverse effects, including the formation of cutaneous squamous cell carcinoma, as well as EMN. We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib.A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident.Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.

  View details for DOI 10.1001/jamadermatol.2014.838

  View details for PubMedID 25142409

• Involution of Eruptive Melanocytic Nevi on Combination BRAF and MEK Inhibitor Therapy JAMA DERMATOLOGY Chen, F. W., Tseng, D., Reddy, S., Daud, A. I., Swetter, S. M. 2014; 150 (11): 1209-1212

  Abstract

  Eruptive melanocytic nevi (EMN) are characterized by the sudden onset of numerous melanocytic nevi and have been traditionally described in the setting of immunosuppression. Selective BRAF inhibitors, such as vemurafenib cause multiple cutaneous adverse effects, including the formation of cutaneous squamous cell carcinoma, as well as EMN. We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib.A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident.Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.

  View details for DOI 10.1001/jamadermatol.2014.838

  View details for Web of Science ID 000346234300020

  View details for PubMedID 25142409

• Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma BRITISH JOURNAL OF DERMATOLOGY Danial, C., Lingala, B., Balise, R., Oro, A. E., Reddy, S., Colevas, A., Chang, A. L. 2013; 169 (3): 673-676

  Abstract

  BACKGROUND: Metastatic basal cell carcinoma (BCC) is a rare but life-threatening condition. Prior estimates of overall survival (OS) from time of diagnosis of distant metastasis to death are approximately 8-14 months. However, these estimates are based on analyses of case reports published prior to 1984. OBJECTIVES: To assess a more updated OS in metastatic BCC patients at a single academic institution. METHODS: Using patients from 1997 to 2011, a retrospective chart review was performed on biopsy-confirmed cases of distant metastatic BCC at Stanford University School of Medicine. Kaplan-Meier analysis was used to determine OS and progression free survival (PFS). RESULTS: Ten consecutive cases of distant metastatic BCC were identified. Median OS was 7.3 (95% confidence interval, CI; 1.6, ∞) years; median PFS was 3.4 (95% CI; 1.1, 5.2) years. CONCLUSION: Our findings suggest that OS in patients with distant metastaticBCC may be more favorable than previously reported.

  View details for DOI 10.1111/bjd.12333

  View details for Web of Science ID 000323700000027

• Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma. British journal of dermatology Danial, C., Lingala, B., Balise, R., Oro, A. E., Reddy, S., Colevas, A., Chang, A. L. 2013; 169 (3): 673-676

  Abstract

  BACKGROUND: Metastatic basal cell carcinoma (BCC) is a rare but life-threatening condition. Prior estimates of overall survival (OS) from time of diagnosis of distant metastasis to death are approximately 8-14 months. However, these estimates are based on analyses of case reports published prior to 1984. OBJECTIVES: To assess a more updated OS in metastatic BCC patients at a single academic institution. METHODS: Using patients from 1997 to 2011, a retrospective chart review was performed on biopsy-confirmed cases of distant metastatic BCC at Stanford University School of Medicine. Kaplan-Meier analysis was used to determine OS and progression free survival (PFS). RESULTS: Ten consecutive cases of distant metastatic BCC were identified. Median OS was 7.3 (95% confidence interval, CI; 1.6, ∞) years; median PFS was 3.4 (95% CI; 1.1, 5.2) years. CONCLUSION: Our findings suggest that OS in patients with distant metastaticBCC may be more favorable than previously reported.

  View details for DOI 10.1111/bjd.12333

  View details for PubMedID 23521172

• A Systemic Complete Response of Metastatic Melanoma to Local Radiation and Immunotherapy TRANSLATIONAL ONCOLOGY Hiniker, S. M., Chen, D. S., Reddy, S., Chang, D. T., Jones, J. C., Mollick, J. A., Swetter, S. M., Knox, S. J. 2012; 5 (6): 404-407

  Abstract

  Melanoma is a relatively immunogenic tumor, in which infiltration of melanoma cells by T lymphocytes is associated with a better clinical prognosis. We hypothesized that radiation-induced cell death may provide additional stimulation of an anti-tumor immune response in the setting of anti-CTLA-4 treatment.In a pilot melanoma patient, we prospectively tested this hypothesis. We treated the patient with two cycles of ipilimumab, followed by stereotactic ablative radiotherapy to two of seven hepatic metastases, and two additional cycles of ipilimumab.Subsequent positron emission tomography-computed tomography scan indicated that all metastases, including unirradiated liver lesions and an unirradiated axillary lesion, had completely resolved, consistent with a complete response by RECIST.The use of radiotherapy in combination with targeted immunotherapy as a noninvasive in vivo tumor vaccine strategy appears to be a promising method of enhancing the induction of systemic immune responses and anti-tumor effect.

  View details for DOI 10.1593/tlo.12280

  View details for PubMedID 23323154

• Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Whittaker, S. J., Demierre, M., Kim, E. J., Rook, A. H., Lerner, A., Duvic, M., Scarisbrick, J., Reddy, S., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Kim, Y. H. 2010; 28 (29): 4485-4491

  Abstract

  The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL).This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells).Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients.Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

  View details for DOI 10.1200/JCO.2010.28.9066

  View details for Web of Science ID 000282643600038

  View details for PubMedID 20697094

• A Phase II Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related Lymphoproliferative Disorders CLINICAL CANCER RESEARCH Duvic, M., Reddy, S. A., Pinter-Brown, L., Korman, N. J., Zic, J., Kennedy, D. A., Lorenz, J., Sievers, E. L., Kim, Y. H. 2009; 15 (19): 6217-6224

  Abstract

  An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30(+) primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF).In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment.The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate.SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study.

  View details for DOI 10.1158/1078-0432.CCR-09-0162

  View details for Web of Science ID 000270498700034

  View details for PubMedID 19789316

• Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma Characterization of Clinical Subset With Worse Outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D. K., Jones, C. R., Vanoli-Storz, M. N., Kohler, S., Reddy, S., Advani, R., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2009: 667–74

  Abstract

  To identify prognostic factors in primary cutaneous anaplastic large cell lymphoma (pcALCL), focusing on extensive limb disease (ELD), defined as initial presentation or progression to multiple skin tumors in 1 limb or contiguous body regions, and to study gene expression profiles of patients with pcALCL.Retrospective cohort study.The Stanford Comprehensive Cancer Center and dermatology ambulatory clinics.A total of 48 patients with pcALCL evaluated from 1990 through 2005.Hazard ratios (HRs) for prognostic factors for overall survival (OS) and disease-specific survival (DSS) and risk factors for progression to extracutaneous disease were identified using Cox regression. Gene expression profiles of 9 typical pcALCL and 3 ELD samples were investigated using complementary DNA microarrays.Univariate analysis demonstrated age, ELD, and progression to extracutaneous disease as significant prognostic factors for OS, whereas ELD and progression to extracutaneous disease were significant for DSS. In multivariate analysis, age (HR, 1.83; 95% confidence interval [CI], 1.02-3.26) and progression to extracutaneous disease (HR, 6.42; 95% CI, 1.39-29.68) remained significant for OS, whereas ELD (HR, 29.31; 95% CI, 1.72-500.82) and progression to extracutaneous disease (HR, 13.12; 95% CI, 1.03-167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a risk factor for progression to extracutaneous disease (HR, 10.20; 95% CI, 1.84-56.72). Microarray data revealed that patients with ELD and typical pcALCL formed distinct clusters.Patients with ELD have a more aggressive course associated with a differential gene expression profile. More aggressive treatments may be indicated for patients with ELD and those whose disease progresses to extracutaneous disease because they have poorer outcomes.

  View details for PubMedID 19528422

• Indolent primary cutaneous B-cell lymphoma: Experience using systemic rituximab JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Morales, A. V., Advani, R., Horwitz, S. M., Riaz, N., Reddy, S., Hoppe, R. T., Kim, Y. H. 2008; 59 (6): 953-957

  Abstract

  Optimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.We sought to assess the efficacy of systemic rituximab in the treatment of CBCL.This was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.Ten patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.The study was limited by the small sample size and retrospective design.This study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

  View details for DOI 10.1016/j.jaad.2008.08.005

  View details for Web of Science ID 000261141600006

  View details for PubMedID 18817999

• Plant-produced idiotype vaccines for the treatment of non-Hodgkin's lymphoma: Safety and immunogenicity in a phase I clinical study PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA McCormick, A. A., Reddy, S., Reinl, S. J., Cameron, T. I., Czerwinkski, D. K., Vojdani, F., Hanley, K. M., Garger, S. J., White, E. L., Novak, J., Barrett, J., Holtz, R. B., Tuse, D., Levy, R. 2008; 105 (29): 10131-10136

  Abstract

  Plant-made vaccines have been the subject of intense interest because they can be produced economically in large scale without the use of animal-derived components. Plant-made therapeutic vaccines against challenging chronic diseases, such as cancer, have received little research attention, and no previous human clinical trials have been conducted in this vaccine category. We document the feasibility of using a plant viral expression system to produce personalized (patient-specific) recombinant idiotype vaccines against follicular B cell lymphoma and the results of administering these vaccines to lymphoma patients in a phase I safety and immunogenicity clinical trial. The system allowed rapid production and recovery of idiotypic single-chain antibodies (scFv) derived from each patient's tumor and immunization of patients with their own individual therapeutic antigen. Both low and high doses of vaccines, administered alone or co-administered with the adjuvant GM-CSF, were well tolerated with no serious adverse events. A majority (>70%) of the patients developed cellular or humoral immune responses, and 47% of the patients developed antigen-specific responses. Because 15 of 16 vaccines were glycosylated in plants, this study also shows that variation in patterns of antigen glycosylation do not impair the immunogenicity or affect the safety of the vaccines. Collectively, these findings support the conclusion that plant-produced idiotype vaccines are feasible to produce, safe to administer, and a viable option for idiotype-specific immune therapy in follicular lymphoma patients.

  View details for DOI 10.1073/pnas.0803636105

  View details for Web of Science ID 000257913200052

  View details for PubMedID 18645180

  View details for PubMedCentralID PMC2481377

• Molecular rescue of tumour-specific T cell receptor idiotype from T cell lymphomas BRITISH JOURNAL OF HAEMATOLOGY Reddy, S. A., Levy, R. 2004; 124 (5): 626-628

  Abstract

  The T cell receptor (TCR) idiotype on T cell lymphomas can serve as a vaccine target. To clone the relevant genes, 5' rapid amplification of cDNA ends (RACE) was performed on 13 T cell lymphomas and nine control samples. Two polymerase chain reactions (PCR) were performed for each TCR chain (alpha and beta) and the proportion of the clonal TCR sequence over the total number of TCR sequences was calculated. For alpha, the average proportions were 0.43 vs. 0.05. For beta these were 0.44 and 0.04. The TCR was identified in 10 of 13 lymphoma samples.

  View details for DOI 10.1111/j.1365-2141.2004.04830.x

  View details for Web of Science ID 000189304300007

  View details for PubMedID 14871249

• CD30(+) cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Liu, H. L., Hoppe, R. T., Kohler, S., Harvell, J. D., Reddy, S., Kim, Y. H. 2003; 49 (6): 1049-1058

  Abstract

  CD30+ cutaneous lymphoproliferative disorders (CLPDs) include lymphomatoid papulosis, borderline cases of CD30+CLPDs, and primary cutaneous anaplastic large cell lymphoma (PCALCL). Prior studies have shown CD30+CLPDs have an excellent prognosis.We sought to present the single-center experience of Stanford University, Stanford, Calif, in the management of CD30+CLPDs.A retrospective cohort analysis of 56 patients with CD30+CLPDs treated at our institution was performed.No patients with lymphomatoid papulosis died of disease, and overall survival was 92% at 5 and 10 years. Disease-specific survivals at 5 and 10 years for PCALCL were 85%. Disease-specific survival at 5 years for localized versus generalized PCALCL was 91% versus 50% (P =.31). PCALCL was highly responsive to treatment, but the relapse rate was 42%. In all, 3 patients progressed to extracutaneous stage of disease. No clinical or histologic factors analyzed were predictive of worse outcome in lymphomatoid papulosis and PCALCL.Similar to prior reports from multicenter European groups, the single-center experience at our institution demonstrates CD30+CLPDs have an overall excellent prognosis; however, cases of PCALCL with poor outcome do exist.

  View details for DOI 10.1016/S0190-9622(03)02484-8

  View details for Web of Science ID 000186784800009

  View details for PubMedID 14639383

• T cell antigen receptor vaccines for active therapy of T cell malignancies Conference on Basic and Clinical Relevant Biology of Cutaneous T Cell Lymphoma Reddy, S. A., Okada, C., Wong, C., Bahler, D., Levy, R. NEW YORK ACAD SCIENCES. 2001: 97–105

  Abstract

  T cell lymphoproliferative disorders continue to be serious management problems, and so alternative therapeutic modalities are continuously being explored. One such strategy involves immunotherapy using the T cell receptor (TCR) as a target. Specifically we are attempting to develop a T cell receptor idiotype (TCR-Id) vaccine because the TCR-Id can serve as a tumor-specific antigen. In this article we will briefly review the rationale for TCR-Id vaccines, the preclinical models as developed in our laboratory, and a discussion of our current plans for a vaccine trial in mycosis fungoides.

  View details for Web of Science ID 000172619000010

  View details for PubMedID 11594586

• Favorable treatment outcome in non-Hodgkin's lymphoma patients with "poor" mobilization of peripheral blood progenitor cells BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Stockerl-Goldstein, K. E., Reddy, S. A., Horning, S. J., Blume, K. G., Chao, N. J., Hu, W. W., JOHNSTON, L. J., Long, G. D., Strober, S., Wong, R. M., Feiner, R. H., Kohler, S., Negrin, R. S. 2000; 6 (5): 506-512

  Abstract

  Our purpose was to evaluate the outcome and costs of high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation in patients with the inability to mobilize sufficient numbers of PBPCs to allow rapid engraftment after PBPC transplantation. We treated 172 consecutive non-Hodgkin's lymphoma (NHL) patients with cyclophosphamide and granulocyte colony-stimulating factor followed by apheresis to collect PBPCs. The cells were separated on a Percoll gradient and purged with monoclonal antibodies and complement. The patients were categorized as "good" mobilizers if a collection of > or =2 x 10(6) CD34+ cells/kg was obtained (n = 138, 80%) or "poor" mobilizers if <2 x 10(6) CD34+ cells/kg were obtained (n = 34, 20%). With a median follow-up of 3.5 years, there is no statistically significant difference in actuarial event-free survival, overall survival, or relapse for good mobilizers compared with poor mobilizers. However, there was a trend toward increasing nonrelapse, transplantation-related mortality of 11.8% for poor mobilizers versus 3.6% for good mobilizers (P = .08) and early death from all causes including relapse within 120 days (poor 20.6% versus good 8.7%, P = .06). The total cost for bone marrow transplantation-related care was significantly higher, at $140,264 for poor mobilizers versus $80,833 for good mobilizers (P = .0001). The population of patients with NHL who mobilize PBPCs poorly into the circulation have a higher cost for posttransplant support. However, there is no significant difference in relapse, event-free survival, or overall survival for such patients compared with those who mobilize PBPCs easily.

  View details for Web of Science ID 000090049700004

  View details for PubMedID 11063379