Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma Authors: Adam D. Cohen1, Noopur Raje2, Jessica A. Fowler3, Khalid Mezzi3, Emma C. Scott3, Madhav V. Dhodapkar4 1Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA. 2Departments of Hematology/Oncology and Medicine, Center for Multiple Myeloma, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 3Amgen, Inc., Thousand Oaks, CA. 4Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA. Running title: Immune Dysfunction and Repurposing T Cells in Myeloma Keywords: Immune Dysfunction; Immuno-Oncology; Myeloma; T cell; Therapy Financial support: This manuscript was sponsored by Amgen Inc. Corresponding author: Adam D. Cohen Department of Medicine, Abramson Cancer Center University of Pennsylvania 3400 Civic Center Blvd. PCAM 12-South, 12-175 Philadelphia, PA 19104 Phone: 215-615-5853 Fax: 215-615-5887 Email: [email protected] 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Disclosure of potential conflicts of interest: A. D. Cohen is a consultant for, and a member of, an advisory board for Celgene and GlaxoSmithKline; is a member of an advisory board for Bristol-Myers Squibb, Janssen, Kite Pharma, Oncopeptides, Seattle Genetics, and Takeda; has received personal fees from Array Biopharma; and has received research funding from Bristol-Myers Squibb and Novartis. N. Raje reports consultancy fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda, and research funding grants from AstraZeneca. J. A. Fowler, K. Mezzi, and E. C. Scott are employees of, and own stock in, Amgen. M. V. Dhodapkar reports consulting fees from Amgen, Celgene, and Janssen. Abstract: 244/250 words Word limit: 2997/3000 Reference limit: 105/105 Figure/Table limit: 5/5 (+2 supplementary) 2 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The progression of multiple myeloma (MM), a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in MM have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in MM, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell–dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell–associated changes during the evolution of MM and provides an overview of T-cell–dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the MM disease continuum; treatment modalities that redirect patient T cells to elicit an anti-MM response, namely chimeric antigen receptor (CAR) T cells and bispecific antibodies (including BiTE® [bispecific T- cell engager] molecules), have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen (BCMA) have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and MM throughout the disease course 3 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. will aid in maximizing the potential for T-cell–dependent immuno-oncology strategies in MM. 4 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Multiple myeloma (MM) is a clonal, multistep, plasma cell malignancy (1, 2). MM often begins with premalignant monoclonal gammopathy of undetermined significance (MGUS), followed by asymptomatic smoldering MM (SMM), and active MM (3). As the disease advances, the immune system demonstrates progressive impairment (4, 5). The introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs) has improved patient outcomes, partially exerting anti-MM activity through immunomodulation (6). Nevertheless, MM remains incurable, becoming more aggressive with poor outcomes when treatment refractoriness occurs (7). The role of T-cell dysfunction in MM and the success of T-cell–directed therapy in other malignancies warrant investigation of treatments enhancing T-cell anti-MM activity (8). This review discusses the role of T cells and T-cell–directed therapies across the MM disease continuum. Evolution of T-cell Immunity in MM Disease Progression Reduced T-cell immunity has been associated with MM disease progression (Figure 1). However, even in patients with MGUS, increased levels of immunosuppressive regulatory T cells (Tregs) (9) and T-cell exhaustion (10) have been reported. An immune profiling study found that T cells from patients with SMM had an aberrant phenotypic profile, including reduced expression of activation markers, compared with those from age-matched healthy controls (5). Early changes in the T-cell population, including the presence of antigen-specific immunity and an enrichment of 5 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. bone marrow (BM) stem-like/resident memory (TRM) T cells may prevent attrition of protective immunity and subsequent disease progression (10-12). Progression to MM has been associated with further immune dysfunction due to an altered T-cell repertoire, with features of terminally differentiated T cells and loss of antigen-specific T-cell function (Figure 1). In MM, loss of stem-like/TRM T cells (10) as well as increases in Tregs (9, 13), and pro-inflammatory Th17 cells (9, 14, 15) have been observed. These changes may have implications for T cell-directed therapy. For example, loss of stem-like/TRM T cells may affect the durability of T-cell redirection or responsiveness to immune checkpoint inhibitors (CPIs). In a study comparing T-cell function in patients with MGUS versus MM, T cells from patients with MM were unable to mount responses to tumor cells (16). This was in contrast to T cells from patients with MGUS, which retained ex vivo anti-tumor activity (16). Taken together, these observations indicate that T cells in MM lose the ability to naturally control tumor progression (16). Several mechanisms for MM-associated reductions in T-cell immunity/responsiveness have been proposed, including T-cell exhaustion, anergy, and/or senescence (17). Reduced T-cell recognition of MM may also be due to ineffective antigen processing/presentation in vivo by tumor cells or dendritic cells (DCs) (18-20). In one study, T cells from MM tumor beds were found to elicit strong, MM- specific cytolytic responses only after ex vivo stimulation with autologous DCs (21). This suggests that endogenous T cells from patients with MM can be activated to mount an antitumor response (21, 22). 6 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 31, 2019; DOI: 10.1158/1078-0432.CCR-19-2111 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. T-cell–Dependent Immuno-Oncology Therapies in MM Understanding the mechanisms affecting T-cell immunity provides opportunities for therapy development. Here, we discuss developments in T-cell–dependent immuno- oncology therapies in MM, including vaccines, CPIs, cellular therapies, and bispecific antibodies (bsAbs)/antibody constructs. MAbs (e.g., daratumumab, elotuzumab, and antibody drug conjugates) and NK cell-based therapies in MM have been recently reviewed (23, 24) and are beyond the scope of this review. Vaccines Anticancer vaccination aims to re-educate