Melody Smith, MD, MS

All Publications

• Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nature medicine Smith, M., Dai, A., Ghilardi, G., Amelsberg, K. V., Devlin, S. M., Pajarillo, R., Slingerland, J. B., Beghi, S., Herrera, P. S., Giardina, P., Clurman, A., Dwomoh, E., Armijo, G., Gomes, A. L., Littmann, E. R., Schluter, J., Fontana, E., Taur, Y., Park, J. H., Palomba, M. L., Halton, E., Ruiz, J., Jain, T., Pennisi, M., Afuye, A. O., Perales, M., Freyer, C. W., Garfall, A., Gier, S., Nasta, S., Landsburg, D., Gerson, J., Svoboda, J., Cross, J., Chong, E. A., Giralt, S., Gill, S. I., Riviere, I., Porter, D. L., Schuster, S. J., Sadelain, M., Frey, N., Brentjens, R. J., June, C. H., Pamer, E. G., Peled, J. U., Facciabene, A., van den Brink, M. R., Ruella, M. 2022

  Abstract

  Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n=228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n=48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

  View details for DOI 10.1038/s41591-022-01702-9

  View details for PubMedID 35288695

• Donor CD19 CART cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity NATURE MEDICINE Ghosh, A., Smith, M., James, S. E., Davila, M. L., Velardi, E., Argyropoulos, K. V., Gunset, G., Perna, F., Kreines, F. M., Levy, E. R., Lieberman, S., Jay, H. V., Tuckett, A. Z., Zakrzewski, J. L., Tan, L., Young, L. F., Takvorian, K., Dudakov, J. A., Jenq, R. R., Hanash, A. M., Motta, A. F., Murphy, G. F., Liu, C., Schietinger, A., Sadelain, M., van den Brink, M. M. 2017; 23 (2): 242-249

  Abstract

  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.

  View details for DOI 10.1038/nm.4258

  View details for Web of Science ID 000393729000016

  View details for PubMedID 28067900

  View details for PubMedCentralID PMC5528161

• CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. Lancet (London, England) Frank, M. J., Baird, J. H., Kramer, A. M., Srinagesh, H. K., Patel, S., Brown, A. K., Oak, J. S., Younes, S. F., Natkunam, Y., Hamilton, M. P., Su, Y. J., Agarwal, N., Chinnasamy, H., Egeler, E., Mavroukakis, S., Feldman, S. A., Sahaf, B., Mackall, C. L., Muffly, L., Miklos, D. B. 2024

  Abstract

  Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

  View details for DOI 10.1016/S0140-6736(24)00746-3

  View details for PubMedID 38996463

• A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

  Abstract

  While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

  View details for DOI 10.1182/blood.2024024952

  View details for PubMedID 38968138

• Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma. Journal for immunotherapy of cancer Bharadwaj, S., Lau, E., Hamilton, M. P., Goyal, A., Srinagesh, H., Jensen, A., Lee, D., Mallampet, J., Elkordy, S., Syal, S., Patil, S., Latchford, T., Sahaf, B., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R., Rezvani, A. R., Shizuru, J., Meyer, E. H., Shiraz, P., Mikkilineni, L., Weng, W. K., Smith, M., Sidana, S., Muffly, L., Maecker, H. T., Frank, M. J., Mackall, C., Miklos, D., Dahiya, S. 2024; 12 (7)

  Abstract

  Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

  View details for DOI 10.1136/jitc-2024-008975

  View details for PubMedID 38955420

• CAR T cell Toxicities: Bedside to Bench - How Novel Toxicities Inform Laboratory Investigations. Blood advances Perna, F., Parekh, S., Diorio, C., Smith, M., Subklewe, M., Mehta, R., Locke, F. L., Shah, N. N. 2024

  Abstract

  Multiple chimeric antigen receptor (CAR) T cell therapies are FDA approved, and several are under development. While effective for some cancers, toxicities remain a limitation. The most common toxicities, i.e. cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), are well described. With increasing utilization, providers worldwide are reporting on other emergent, and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalogue these emerging and emergent CAR T toxicities and describe management approaches, the American Society of Hematology Subcommittee on Emerging Gene and Cell Therapies organized the first Scientific Workshop on CAR T cell toxicities during the annual society meeting. The workshop functioned to 1) aggregate reports of CAR T emergent toxicities, including movement disorders after BCMA CAR T, coagulation abnormalities, and prolonged cytopenias; 2) disseminate bedside to bench efforts elucidating pathophysiological mechanisms of CAR-T toxicities, including the intestinal microbiota and systemic immune dysregulation; and 3) highlight gaps in the availability of clinical tests such as cytokine measurements, which could be utilized to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, while clinical manifestations may develop before the pathophysiologic mechanisms are understood, these must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears central to these emergent toxicities and research is needed to elucidate links between tumor, CAR T, and microbiota. Finally, there was consensus around an urgency to create a repository to capture emergent CAR-T toxicities and the real-world management.

  View details for DOI 10.1182/bloodadvances.2024013044

  View details for PubMedID 38861351

• Recruitment and Retention of Hematopoietic Cell Transplantation and Cellular Therapy Physicians: A Report from the ASTCT Talent Acquisition Task Force. Transplantation and cellular therapy Sharma, A., Czechowicz, A., Mavers, M., Chao, N., DiPersio, J., Reddy, P., Perales, M. A., Smith, M. 2024

  Abstract

  A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years.American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT.This was a cross sectional survey conducted via emails sent to the ASTCT membership.Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose to burnout.A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention to the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds.

  View details for DOI 10.1016/j.jtct.2024.04.005

  View details for PubMedID 38608806

• An Assessment of CAR-T Cell Therapy Utilization among Racial and Ethnic Minority Patients. NEJM evidence Hill, L. C., Smith, M. 2024; 3 (4): EVIDe2400022

  View details for DOI 10.1056/EVIDe2400022

  View details for PubMedID 38805616

• CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity. Blood advances Hamilton, M. P., Craig, E., Gentille Sanchez, C., Mina, A., Tamaresis, J., Kirmani, N., Ehlinger, Z., Syal, S., Good, Z., Sworder, B., Schroers-Martin, J., Lu, Y., Muffly, L., Negrin, R. S., Arai, S., Lowsky, R., Meyer, E., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Kurtz, D. M., Mackall, C. L., Tibshirani, R., Alizadeh, A. A., Frank, M. J., Miklos, D. B. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

  View details for DOI 10.1182/bloodadvances.2024012637

  View details for PubMedID 38498731

• Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease. Nature microbiology Lindner, S., Miltiadous, O., Ramos, R. J., Paredes, J., Kousa, A. I., Dai, A., Fei, T., Lauder, E., Frame, J., Waters, N. R., Sadeghi, K., Armijo, G. K., Ghale, R., Victor, K., Gipson, B., Monette, S., Russo, M. V., Nguyen, C. L., Slingerland, J., Taur, Y., Markey, K. A., Andrlova, H., Giralt, S., Perales, M. A., Reddy, P., Peled, J. U., Smith, M., Cross, J. R., Burgos da Silva, M., Campbell, C., van den Brink, M. R. 2024

  Abstract

  Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

  View details for DOI 10.1038/s41564-024-01617-w

  View details for PubMedID 38429422

  View details for PubMedCentralID 4056765

• Clinical Features of Neurotoxicity Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma. Blood advances Nie, E. H., Su, Y. J., Baird, J. H., Agarwal, N., Bharadwaj, S., Weng, W. K., Smith, M., Dahiya, S., Han, M. H., Dunn, J. E., Kipp, L. B., Miklos, D. B., Scott, B. J., Frank, M. J. 2024

  Abstract

  CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

  View details for DOI 10.1182/bloodadvances.2023011896

  View details for PubMedID 38295285

• Microbes matter in pediatric allo-HSCT. Blood Smith, M., Markey, K. A. 2023; 142 (16): 1335-1337

  View details for DOI 10.1182/blood.2023021608

  View details for PubMedID 37856093

• How I Treat Refractory CRS and ICANS Following CAR T-cell Therapy. Blood Jain, M. D., Smith, M., Shah, N. N. 2023

  Abstract

  The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly due to expanding indications for standard of care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential to facilitating the widespread use. Pre-emptive interventions to prevent more severe toxicities has improved safety, facilitating CAR T-cell therapy in medically frail populations and those at high-risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic, as it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk-factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.

  View details for DOI 10.1182/blood.2022017414

  View details for PubMedID 36989488

• Harnessing ADR T cells to enhance allo-HCT. Blood Smith, M. 2023; 141 (10): 1101-1102

  View details for DOI 10.1182/blood.2022018182

  View details for PubMedID 36893007

• Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nature medicine Smith, M., Dai, A., Ghilardi, G., Amelsberg, K. V., Devlin, S. M., Pajarillo, R., Slingerland, J. B., Beghi, S., Herrera, P. S., Giardina, P., Clurman, A., Dwomoh, E., Armijo, G., Gomes, A. L., Littmann, E. R., Schluter, J., Fontana, E., Taur, Y., Park, J. H., Palomba, M. L., Halton, E., Ruiz, J., Jain, T., Pennisi, M., Afuye, A. O., Perales, M., Freyer, C. W., Garfall, A., Gier, S., Nasta, S., Landsburg, D., Gerson, J., Svoboda, J., Cross, J., Chong, E. A., Giralt, S., Gill, S. I., Riviere, I., Porter, D. L., Schuster, S. J., Sadelain, M., Frey, N., Brentjens, R. J., June, C. H., Pamer, E. G., Peled, J. U., Facciabene, A., van den Brink, M. R., Ruella, M. 2022

  View details for DOI 10.1038/s41591-022-02069-7

  View details for PubMedID 36253610

• Burnout in U.S. hematologists and oncologists: impact of compensation models and advanced practice provider support. Blood advances Lee, A. I., Masselink, L. E., De Castro, L. M., Marshall, A. L., Connell, N. T., Dent, G. A., Fritz, J., Homer, M. R., Lucas, T. L., Naik, R. P., Nelson, M., O'Connell, C. L., Rajasekhar, A., Reynolds, R. J., Sharma, D., Smith, M., Weeks, L. D., Erikson, C. E. 2022

  Abstract

  Burnout is prevalent in throughout medicine. Few large-scale studies have examined the impact of physician compensation or clinical support staff on burnout among hematologists and oncologists. In 2019, the American Society of Hematology conducted a practice survey of hematologists and oncologists in the American Medical Association Masterfile; burnout was measured using a validated, single-item burnout instrument from the Physician Work Life Study, while satisfaction was assessed in several domains using a 5-point Likert scale. The overall survey response rate was 25.2% (N = 631). Of 411 respondents with complete responses in the final analysis, 36.7% (N = 151) were from academic practices and 63.3% (N = 260) from community practices; 29.0% (N = 119) were female. Over one-third (36.5%; N = 150) reported burnout, while 12.0% (N = 50) had a high level of burnout. In weighted multivariate logistic regression models incorporating numerous variables, compensation plans based entirely on relative value unit (RVU) generation were significantly associated with high burnout among academic and community physicians, while the combination of RVU + salary compensation showed no significant association. Female gender was associated with high burnout among academic physicians. High advanced practice provider utilization was inversely associated with high burnout among community physicians. Distinct patterns of career dissatisfaction were observed between academic and community physicians. We propose that implementation of compensation models not based entirely on clinical productivity, increased support for women in academic medicine, and expansion of advanced practice provider support in community practices may address burnout among hematologists and oncologists.

  View details for DOI 10.1182/bloodadvances.2021006140

  View details for PubMedID 35476017

• Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL. Frontiers in immunology Jeyakumar, N., Smith, M. 2022; 13: 887866

  Abstract

  Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients' eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naive/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.

  View details for DOI 10.3389/fimmu.2022.887866

  View details for PubMedID 35663947

• The Composition of the Intestinal Microbiota Correlates with Response and Toxicity after CAR T cell Immunotherapy in Patients with B-cell Malignancies Smith, M. Nature Medicine . 2021
• A Question of Beneficence: Comorbidity Assessment to Ascertain Potential Benefit of CD19 Chimeric Antigen Receptor T Cells for Patients with Diffuse Large B Cell Lymphoma TRANSPLANTATION AND CELLULAR THERAPY Smith, M. 2021; 27 (1): 2-3

  View details for DOI 10.1016/j.jtct.2020.11.002

  View details for Web of Science ID 000619132900027

• Relapse after allogeneic stem cell transplantation of acute myeloid leukemia and myelodysplastic syndrome and importance of second cellular therapy. Smith, M. Transplantation and Cellular Therapy. 2021
• Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109a induce less graft-versus-host disease Smith, M. Blood. 2021
• The gut microbiota is associated with immune cell dynamics in humans NATURE Schluter, J., Peled, J. U., Taylor, B. P., Markey, K. A., Smith, M., Taur, Y., Niehus, R., Staffas, A., Dai, A., Fontana, E., Amoretti, L. A., Wright, R. J., Morjaria, S., Fenelus, M., Pessin, M. S., Chao, N. J., Lew, M., Bohannon, L., Bush, A., Sung, A. D., Hohl, T. M., Perales, M., van den Brink, M. M., Xavier, J. B. 2020; 588 (7837): 303-307

  Abstract

  The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.

  View details for DOI 10.1038/s41586-020-2971-8

  View details for Web of Science ID 000592644600005

  View details for PubMedID 33239790

  View details for PubMedCentralID PMC7725892

• Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies BLOOD ADVANCES Jain, T., Knezevic, A., Pennisi, M., Chen, Y., Ruiz, J. D., Purdon, T. J., Devlin, S. M., Smith, M., Shah, G. L., Halton, E., Diamonte, C., Scordo, M., Sauter, C. S., Mead, E., Santomasso, B. D., Palomba, M., Batlevi, C. W., Maloy, M. A., Giralt, S., Smith, E., Brentjens, R., Park, J. H., Perales, M., Mailankody, S. 2020; 4 (15): 3776-3787

  Abstract

  Factors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had "recovered" (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell-associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies.

  View details for DOI 10.1182/bloodadvances.2020002509

  View details for Web of Science ID 000560095100034

  View details for PubMedID 32780846

  View details for PubMedCentralID PMC7422135

• Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nature immunology Vardhana, S. A., Hwee, M. A., Berisa, M., Wells, D. K., Yost, K. E., King, B., Smith, M., Herrera, P. S., Chang, H. Y., Satpathy, A. T., van den Brink, M. R., Cross, J. R., Thompson, C. B. 2020

  Abstract

  The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

  View details for DOI 10.1038/s41590-020-0725-2

  View details for PubMedID 32661364

• Associations between hematology/oncology fellows' training and mentorship experiences and hematology-only career plans BLOOD ADVANCES Masselink, L. E., Erikson, C. E., Connell, N. T., De Castro, L. M., Dent, G. A., Marshall, A. L., Naik, R. P., Nelson, M., O'Connell, C. L., Rajasekhar, A., Sharma, D., Smith, M., Lee, A. 2019; 3 (21): 3278-3286

  Abstract

  As the adult hematology and oncology fellowship training pathways have merged in the United States and concerns have arisen about the aging of practicing hematologists, the American Society of Hematology and hematology education leaders are looking to improve their understanding of the factors that contribute to fellows' plans to enter hematology-only careers. With the support of the American Society of Hematology, we collected and analyzed data from a survey of hematology/oncology fellows (n = 626) to examine the relationship between training and mentorship experiences and fellows' plans to enter hematology-only careers. Fellows who planned to enter hematology-only careers were significantly more likely to report having clinical training and mentorship experiences in hematology throughout their training relative to fellows with oncology-only or combined hematology/oncology career plans. After controlling for prior interest in hematology and demographic characteristics, exposure to hematology patients in medical school and fellowship, hematology research experiences, and hematology mentorship (research collaboration and career coaching) were positively and significantly associated with hematology-only career plans. These findings suggest that increasing opportunities for exposure to hematology patients, research opportunities and mentors throughout training could be helpful in building a strong pipeline of potential hematologists.

  View details for DOI 10.1182/bloodadvances.2019000569

  View details for Web of Science ID 000496921800011

  View details for PubMedID 31698456

  View details for PubMedCentralID PMC6855099

• Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34(+) Selected Allogeneic Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Scordo, M., Bhatt, V., Hilden, P., Smith, M., Thoren, K., Cho, C., Shah, G. L., Maloy, M. A., Papadopoulos, E. B., Jakubowski, A. A., Avecilla, S. T., O'Reilly, R. J., Castro-Malaspina, H., Tamari, R., Shaffer, B. C., Boelens, J. J., Perales, M., Giralt, S. A. 2019; 25 (8): 1526-1535

  Abstract

  Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.

  View details for DOI 10.1016/j.bbmt.2019.02.021

  View details for Web of Science ID 000483008500008

  View details for PubMedID 30831208

  View details for PubMedCentralID PMC7302932

• Posttransplant chimeric antigen receptor therapy BLOOD Smith, M., Zakrzewski, J., James, S., Sadelain, M. 2018; 131 (10): 1045-1052

  Abstract

  Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

  View details for DOI 10.1182/blood-2017-08-752121

  View details for Web of Science ID 000430687200004

  View details for PubMedID 29358181

  View details for PubMedCentralID PMC5865610

• Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia. Biology of blood and marrow transplantation Hamilton, B. K., Rybicki, L., Abounader, D., Adekola, K., Advani, A., Aldoss, I., Bachanova, V., Bashey, A., Brown, S., DeLima, M., Devine, S., Flowers, C. R., Ganguly, S., Jagasia, M., Kennedy, V. E., Kim, D. D., McGuirk, J., Pullarkat, V., Romee, R., Sandhu, K., Smith, M., Ueda, M., Viswabandya, A., Vu, K., Wall, S., Zeichner, S. B., Perales, M., Majhail, N. S. 2017

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.

  View details for DOI 10.1016/j.bbmt.2017.04.003

  View details for PubMedID 28396160

• Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis LEUKEMIA Landau, H., Smith, M., Landry, C., Chou, J. F., Devlin, S. M., Hassoun, H., Bello, C., Giralt, S., Comenzo, R. L. 2017; 31 (1): 136-142

  Abstract

  Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with

  View details for DOI 10.1038/leu.2016.229

  View details for Web of Science ID 000394058700018

  View details for PubMedID 27560108

  View details for PubMedCentralID PMC5220129

• Tumor immunology and cancer immunotherapy: summary of the 2014 SITC primer JOURNAL FOR IMMUNOTHERAPY OF CANCER Page, D. B., Bourla, A., Daniyan, A., Naidoo, J., Smith, E., Smith, M., Friedman, C., Khalil, D. N., Funt, S., Shoushtari, A. N., Overwijk, W. W., Sharma, P., Callahan, M. K. 2015; 3

  View details for DOI 10.1186/s40425-015-0072-2

  View details for Web of Science ID 000363741800004

• Racial Differences in the Presentation and Outcomes of Chronic Lymphocytic Leukemia and Variants in the United States CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Shenoy, P. J., Malik, N., Sinha, R., Nooka, A., Nastoupil, L. J., Smith, M., Flowers, C. R. 2011; 11 (6): 498-506

  Abstract

  Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the United States, and prolymphocytic leukemia (PLL) is a related, rare chronic lymphoproliferative disorder.Using the United States Surveillance, Epidemiology and End Results (SEER) data from 13 registries, we examined differences in incidence and survival for CLL, small lymphocytic lymphoma (SLL) and PLL by race. International Classification of Diseases for Oncology 3(rd) edition histology codes 9670, 9823, and 9632-34 were used to identify cases.From 1992 to 2007, 30,622 cases of CLL/SLL and 268 cases of PLL were recorded. Males had higher incidence than females (male-to-female incidence rate ratio CLL/SLL 1.89, 95% confidence interval (CI) 1.85-1.94 and PLL 2.47, 95%CI 1.90-3.20). Black patients were diagnosed at younger age compared to white patients (mean age at diagnosis for white versus black patients for CLL/SLL, 70 versus 67 years, P < .001; for PLL, 71 versus 61 years, P < .001). Greater proportion of black patients with SLL presented with B symptoms, extranodal primary site, and advanced disease compared to white patients (P = .003, P = .012, and P = .009 respectively). White patients with CLL/SLL had better survival rates than black patients (5-year relative survival rate 77.1% versus 63.9%, P < .01). In univariate Cox regression models, black race, male gender, age at diagnosis > 65 years, advanced stage, and B-symptoms were predictors of worse survival (P < .01) among CLL/SLL patients.Black patients with CLL/SLL and PLL present at younger age and black patients with CLL/SLL have worse survival than white patients. Epidemiological studies examining the biological variants of these diseases in concert with race are needed to elucidate the etiology of these disparities.

  View details for DOI 10.1016/j.clml.2011.07.002

  View details for Web of Science ID 000298280200007

  View details for PubMedID 21889433

• Both naive and memory T cells exert alloreactivity across HLA barriers Smith, M. Biology of Blood and Marrow Transplantation. 2011
• Clinical, Molecular, and Environmental Risk Factors for Hodgkin Lymphoma Smith, M. Advances in Hematology. 2011