Review
Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors

https://doi.org/10.1016/j.clml.2017.06.014Get rights and content

Abstract

Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti–PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.

Introduction

There have been significant advances in the understanding of the biology of multiple myeloma (MM) in recent years. In the classic view of the pathogenesis of MM, an initiating hit is necessary to immortalize a myeloma-propagating cell. This cell then acquires additional genetic hits over time, mediated by translocation, loss of heterozygosity, gene amplification, mutation, or epigenetic changes, which further deregulate the behavior of the MM-propagating cell, leading step by step to the well-known MM features.1 Many of the genes and pathways mediating this transformation process have now been characterized. Nevertheless, disease progression is not only the consequence of intrinsic tumor changes. Interactions between the tumor and the microenvironment in which the cancer grows play an essential role,2 and the focus of studies has shifted from the disease itself alone to the disease in the context of the microenvironment in which the tumor grows. The immune system is an important component of the tumor microenvironment in MM, as well as in many other cancers, and is the focus of the immune-oncology approach.

Section snippets

Rationale for Immune-oncology

The immune system can potentially recognize and reject the tumor. Tumor cells can express aberrant antigens; that is, molecules expressed in tumor cells, but not in normal cells. These can be normal cellular proteins that are abnormally expressed as a result of genetic mutations, quantitative differences in expression, or differences in posttranslational modifications.3 In tumor types that have a well-documented viral origin, viral proteins also can serve as tumor antigens.4, 5 Tumor antigens

Immune-oncologic Approach in MM

Immune therapy can be directed against the tumor itself or toward immune cells. There are 2 strategies to act toward immune cells and boost antitumor immunity: one consists of increasing antitumor activity (acting on T and NK cytotoxic cells), the other in reducing immunosuppression (acting on MDSCs and Tregs). Treatment approaches include monoclonal antibodies (mAbs) targeting surface molecules present on MM cells, mAbs targeting checkpoint inhibitors on immune cells/tumor cells,

Conclusion

Advances in the understanding of MM biology and its clinical management have recently led to an increased survival rate, reaching up to 8 to 10 years. Several new agents, with different mechanisms of action and different targets, have increased the treatment armamentarium against a complex disease such as MM. These agents include chemotherapeutic agents, immunomodulatory drugs, and proteasome inhibitors, which are currently considered the backbone treatments for MM. Other agents more recently

Disclosure

Francesca Gay has served on the advisory board of Takeda, Seattle Genetics, and Roche, and received honoraria from Takeda, Amgen, Celgene, Janssen, and BMS. The other authors declare no potential conflicts.

References (81)

  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • A. Bashey et al.

    CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation

    Blood

    (2009)
  • E.A. Tivol et al.

    Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

    Immunity

    (1995)
  • J.P. Allison

    CD28-B7 interactions in T-cell activation

    Curr Opin Immunol

    (1994)
  • H. Nishimura et al.

    Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor

    Immunity

    (1999)
  • J. Liu et al.

    Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway

    Blood

    (2007)
  • W.H.D. Hallett et al.

    Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade

    Biol Blood Marrow Transplant

    (2011)
  • D.M. Benson et al.

    A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma

    Blood

    (2012)
  • E. Carbone et al.

    HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells

    Blood

    (2005)
  • P.R. Tembhare et al.

    Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases

    Leuk Res

    (2014)
  • S.A. Ali et al.

    T cells expressing an anti-B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple myeloma

    Blood

    (2016)
  • J.G. Berdeja et al.

    Clinical remissions and limited toxicity in a first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma

    Eur J Cancer

    (2016)
  • J. Vera et al.

    T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

    Blood

    (2006)
  • J.N. Brudno et al.

    Toxicities of chimeric antigen receptor T cells: recognition and management

    Blood

    (2016)
  • G.J. Morgan et al.

    How to use new biology to guide therapy in multiple myeloma

    Hematology Am Soc Hematol Educ Program

    (2012)
  • C. Zelle-Rieser et al.

    T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

    J Hematol Oncol

    (2016)
  • G. Dranoff

    Cytokines in cancer pathogenesis and cancer therapy

    Nat Rev Cancer

    (2004)
  • M.-H. Chang

    Cancer prevention by vaccination against hepatitis B

    Recent Results Cancer Res

    (2009)
  • G.G. Kenter et al.

    Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia

    N Engl J Med

    (2009)
  • R.D. Schreiber et al.

    Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

    Science

    (2011)
  • W. Zou

    Regulatory T cells, tumour immunity and immunotherapy

    Nat Rev Immunol

    (2006)
  • A. Romano et al.

    Immunological dysregulation in multiple myeloma microenvironment

    Biomed Res Int

    (2014)
  • M.K. Brimnes et al.

    Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma

    Clin Exp Immunol

    (2006)
  • H. Nishikawa et al.

    Regulatory T cells in tumor immunity

    Int J Cancer

    (2010)
  • P.C. Rodriguez et al.

    Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses

    Cancer Res

    (2004)
  • M.-E. Cruz-Munoz et al.

    Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function

    Nat Immunol

    (2009)
  • S. Lonial et al.

    Elotuzumab therapy for relapsed or refractory multiple myeloma

    N Engl J Med

    (2015)
  • P. Lin et al.

    Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma

    Am J Clin Pathol

    (2004)
  • M. de Weers et al.

    Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors

    J Immunol

    (2011)
  • M.B. Overdijk et al.

    Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

    MAbs

    (2015)
  • Cited by (0)

    View full text