The Hematologist

May-June 2018, Volume 15, Issue 3

Immunotherapy in Multiple Myeloma: The Era of CAR T Cell Therapy

Tarek H. Mouhieddine, MD Postdoctoral Research Fellow, Department of Medical Oncology
Dana-Farber Cancer Institute, Boston, MA
Irene M. Ghobrial, MD Associate Professor of Medicine
Harvard Medical School; Dana Farber Cancer Institute, Boston, MA

Published on: April 02, 2018

Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood. 2017;130:740.

For more than a decade, the standard of care for treating multiple myeloma has included novel therapeutic agents with the use of immunomodulatory drugs (IMiDs) and proteasome inhibitors along with autologous stem-cell transplantation (ASCT).1 However, recent advances in immunotherapy have paved the way to develop novel agents that re-educate the immune system to effectively target the tumor clone. Chimeric antigen receptor (CAR) T cell therapy2,3 reprograms the patient’s T cells to target tumor-associated antigens such as CD19 as in the case of the recently U.S. Food and Drug Administration–approved CAR T cell therapies: Tisagenlecleucel for recurrent pediatric acute lymphoblastic leukemia (ALL) and axicabtagene ciloleucel for certain recurrent adult B cell lymphomas.

After the great of success CAR T cell therapy in ALL, more research is currently underway to extend this treatment to other hematologic malignancies, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). There are currently 27 registered CAR T clinical trials, 20 of which are specific for MM and 16 of which are in the United States alone.4 Similar to other hematologic malignancies, CAR T cell therapy in MM began with targeting CD19, which unfortunately did not yield a sustained clinical response following ASCT,5 likely because of the low expression of CD19 on the surface of MM cells. Similarly, targeting CD138,6 and the kappa light chain7 of plasma cells led to modest responses owing to low potency and inability of plasma cells to retain surface expression of immunoglobulins, respectively.

Current studies and clinical trials are focused on targeting BCMA, a TNF receptor superfamily 17, that is exclusively upregulated in B cells differentiating into plasma cells.8 After the first BCMA CAR T cell therapy clinical trial was conducted with promising outcomes,9 other trials targeting the same antigen followed suit. A single-arm clinical trial on BCMA CAR T cell therapy in relapsed/refractory MM presented its results at the 2017 American Society of Clinical Oncology Annual Meeting, indicating that 18 (95%) of their 19 patients who received a median infusion cell number of 4.7 (0.6-7.0) × 106/kg, achieved complete remission (CR) throughout a median follow-up of 208 (62-321) days, with the majority (14 of 19) experiencing manageable cytokine release syndrome (CRS).10

Most notable perhaps, is the recent phase I clinical trial published by Dr. Jesus Berdeja and colleagues, which revealed that 15 (71%) of 21 MM patients who failed a median of seven lines of treatment experienced CRS following CAR T cell infusion. In this study, the authors used bb2121, a novel CAR that incorporates an anti-BCMA single-chain variable fragment, a 4-1BB costimulatory motif, and a CD3-zeta T cell activation domain. Moreover, from 18 patients who received a high infusion dose, a good treatment response was observed in 17, with 10 achieving CR at a median follow-up of 40 weeks. This sparked the launch of the phase II KarMMa trial to investigate the difference in response to an infusion of 150 versus 300 million CAR T cells.

From there, mechanisms of relapse and resistance to anti-BCMA CAR T cell therapy, and the possibility of devising a potent combination of CAR T cells and a chemotherapeutic regimen require further study. Another study presented at the 2017 ASH Annual Meeting compared the response of highly refractory MM patients with high-risk cytogenetics to CAR T cells at different infusion dosages with and without lymphodepletion with cyclophosphamide.11 Indeed, they found that a lower infusion dose led to lower response rates and efficacy, while the addition of cyclophosphamide to the regimen led to a higher median peak expansion of CAR T–BCMA cells, which is associated with achieving a partial response or better. Furthermore, another pilot trial of eight patients simultaneously used both anti-CD19 and BCMA CAR T cells in addition to cyclophosphamide.12 While this study demonstrated clinical benefit and collateral toxicities (CRS and prolonged cytopenias) similar to other trials, the small patient number and short follow-up of four weeks prevents them from drawing concrete conclusions at this point. Yet, this study addresses a main concern, which is the possibility of CAR T–BCMA–induced immune editing whereby residual MM cells decrease their BCMA expression following CAR T cell infusion, enabling immune evasion. Therefore, using a dual- or even triple-targeting CAR could potentially overcome this problem and enhance the response rate to CAR T cell therapy. To address the issue of CRS, which has been the most common side effect in all trials, another study presented at the 2017 ASH Annual Meeting demonstrated the possibility of generating CD8+ anti-BCMA CAR T cells via mRNA transfection rather than viral gene transduction that causes uncontrolled in vivo expansion of permanently modified CART cells, thereby increasing the risk of CRS and neurotoxicity.13 Their transfected CD8+ T cells demonstrated a dose-dependent efficacy in a disseminated human MM model as well as a reduced secretion of interferon-γ, a key cytokine in CRS.

The field of immunotherapy in MM is gaining momentum in the direction of CAR T cell therapy, as more preclinical and clinical trials are initiated to study different infusion dosages and drug combinations, as well as single versus multiple CAR specificities. The mere fact that we are witnessing a substantial treatment response to CAR T cell therapy in those who have failed a median of seven or more lines of treatment predicts the possibility of a revolutionary breakthrough in MM treatment. It would not be surprising to see this promising treatment being administered in the next few years to treatment-naïve newly diagnosed MM cases with high risk features and poor prognosis with current standard of care.

References

  1. Dimopoulos MA, Richardson PG, Moreau P, et al. Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol. 2015;12:42-54.
  2. Khalil DN, Smith EL, Brentjens RJ, et al. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273-290.
  3. Themeli M, Rivière I, Sadelain M. New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell. 2015;16:357-366.
  4. 2018 Car-T; multiple myeloma. ClinicalTrials.gov.
  5. Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040-1047.
  6. Guo B, Chen M, Han Q, et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J Cell Immun. 2016;2:28-35.
  7. Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016;126:2588-2596.
  8. Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7:1187-1199.
  9. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128:1688-1700.
  10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2018; doi: 10.1200/JCO.2017.35.18_suppl.LBA3001. [Epub ahead of print].
  11. Cohen AD, Garfall AL, Stadtmauer EA, et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood. 2017;130:505.
  12. Yan L, Shang J, Kang L, et al. Combined infusion of CD19 and Bcma-specific chimeric antigen receptor T cells for RRMM: initial safety and efficacy report from a clinical pilot study. Blood. 2017;130:506.
  13. Lin L, Xing L, Acharya CM, et al. CD8+ anti-BCMA mRNA CAR T-cells effectively kill human multiple myeloma cells in vitro and in vivo. Blood. 2017;130:3067.

Conflict of Interests

Dr. Ghobrial and Dr. Mouhieddine indicated no relevant conflicts of interest. back to top