Novel Therapeutic Approaches in Multiple Myeloma: The Future of CAR T-Cells
Professor of Medicine
Harvard Medical School
Director, Center for Multiple Myeloma
Massachusetts General Hospital
Can you provide some background on CAR T-cell therapy and an overview of its possible role in the treatment of MM?
Chimeric antigen receptor (CAR) T-cell therapy was first investigated as a treatment for acute leukemia and B-cell lymphomas several years ago,1 and two such agents have been approved by the Food and Drug Administration (FDA) for these diseases. Since that time, investigators have begun assessing the role of CAR T-cell therapy in the treatment of MM.
CARs are engineered ex vivo to target an antigen that is restricted to tumor cells and should not be expressed on normal cells. For example, the CARs that are used for treating leukemia target CD19, which is expressed from leukemia cells, and CARs targeting CD20 are being investigated in lymphoma.2
In myeloma, CAR T-cell therapy is being used to specifically target the B-cell maturation antigen (BCMA), which is expressed as B-cells become mature plasma cells.3 BCMA is also expressed on normal plasma cells, but it is mostly restricted to myeloma plasma cells and is not typically present on other cell types. Most of the CARs currently in development in the context of myeloma have been targeted against BCMA.3
With CAR T-cell therapy, the CAR T-cells must be activated in order for treatment to be effective.4 Several different CAR T-cell therapies have been tried in MM, with each using various co-stimulatory molecules, such as 4-1BB and CD28. Some of the CAR T-cell therapies in phase 1 clinical trials include bb2121, anti-BCMA CAR, LCAR-B38M, CART-BCMA, and EGFRt/BCMA-41BBz, while others are in the preclinical trial phase (see Table).3
|Table: CAR T-cell Therapies
Targeting BCMA in MM3
Can you describe recent clinical trial data evaluating CAR T-cell therapy as a treatment for MM and highlight important findings from this research?
Several CAR T products are currently being tested in clinical trials as a potential treatment for MM, but the one that appears to be furthest along in development is bb2121, a second-generation CAR T-cell therapy. A phase 1 trial (NCT02658929) has been conducted to assess the safety and efficacy of bb2121 in 43 MM patients who had relapsed/refractory disease, accruing a follow-up of more than one year. Participants in this trial were heavily pretreated, having endured seven or eight lines of previous treatment, on average. Most patients in the trial had one stem cell transplant, but some had two. These individuals still developed relapsed/refractory MM despite having received all of the currently approved therapies for the disease. The CAR T-cell generation rate in this clinical trial was 100%.5
Once CARs were generated, the trial assessed if they were safe to use. When the approach of using CAR T-cells was first conceived in acute leukemia, there were concerns about cytokine release syndrome (CRS) and neurotoxicity. MM is different because, unlike the leukemia population, patients with the disease tend to be older with more comorbidities. Initially, there were tolerability concerns, but data regarding the safety of bb2121 were encouraging. CRS did occur in some patients, but it was low-grade in about 70% of cases, manifesting mostly as fevers. Aggressive treatment of CRS with tocilizumab was required in fewer than 30% of patients in the phase 1 bb2121 trial. To date, only one patient was affected by neurotoxicity and has recovered completely. In total, the early data suggest that this CAR T-cell therapy appears to have a reasonable safety profile.5
The most encouraging findings observed with bb2121 in MM patients were that the treatment correlated with many complete responses and stringent complete responses as well as participants becoming minimal residual disease (MRD) negative. These results were unexpected considering that patients were so heavily pretreated. The median progression-free survival (PFS) of all patients in the trial was close to 12 months, but the PFS increased to 17 months for those who achieved MRD negative disease.5 These efficacy data, taken together with a manageable toxicity profile, have set the stage for further exploration of CAR T-cell therapy in MM. Other forthcoming trials are being designed to begin CAR T-cell therapy earlier in the disease course to determine if more durable responses can be achieved.
Unlike many of the leukemia and lymphoma trials assessing CAR T-cell therapy, studies of this treatment in MM have not used an absolute lymphocyte count cutoff. Despite this, investigations have shown that CARs could still been generated in essentially all patients. This is an important note because MM patients in the clinical trials for bb2121 had received immunosuppressive therapy for 6 to 10 years. It is possible that immunosuppressive treatments facilitated the observed durable remissions observed in trials and lasted for about one year. If CAR T-cell therapy can be started earlier in the disease course, at a time when patients are less exposed to other more toxic drugs, remission duration might improve to a greater extent, but more trials are needed to test this hypothesis.
What is known about how CAR T-cell therapy for MM may interact with agents that are being used for conditioning chemotherapy?
Clinical trials assessing the bb2121 CAR T-cell therapy in MM were designed in a way that participants received low doses of cyclophosphamide and fludarabine to lymphodepleted patients and to get rid of their immunosuppressive cells, such as myeloid suppressor cells and T-regulatory cells, prior to giving reengineered T-cells. The purpose of this course of action was to ensure that the CAR T-cells would have their greatest impact on the disease. This is a very different purpose than conditioning chemotherapy, which is typically designed for use in the setting of an autologous stem cell transplant. Most of the MM patients in trials for CAR T-cell therapy have already previously had a transplant, but this has not interfered with the ability of researchers to generate CARs.
How can clinicians determine if their MM patients are candidates for a clinical trial investigating CAR T therapy?
For many MM patients, it is challenging to enter a CAR T-cell therapy study protocol because space is limited and competition is fierce. Community oncologists should seek to refer MM patients early to centers that are conducting trials for CAR T-cell therapy rather than waiting for all treatment options to be exhausted. This is not a therapy that can be taken off the shelf and given to patients the next day. In most cases, the CAR T-cell reengineering process takes roughly 4 to 6 weeks. In addition, clinicians must consider various patient factors to determine the optimal bridging therapy. Coordination between community oncologists and the academic centers offering these treatments is critical to ensuring that patients have the opportunity to be involved with a clinical trial for CAR T-cell therapy.
Oncologists and their patients must understand that CAR T-cell therapy is not an autologous stem cell transplant. This is a unique treatment strategy that does not involve myeloablative doses of chemotherapy and their expected toxicities, such as CRS and neurotoxicity. Treatment with CAR T-cell therapy will be different than what is seen in the transplant world. Another important note is that CAR T-cells have been used in many older patients, including those who are well into their 70s. As long as these patients are otherwise healthy, it is likely they will be able to tolerate the procedure quite well. Furthermore, patients are currently required to be admitted to the treating institution in clinical trials evaluating CAR T-cell therapy, but it is possible that this treatment could eventually become an outpatient procedure. For this to happen, plenty of support and a sound infrastructure must be in place.
What key take-home messages should community oncologists recognize regarding the utility of CAR T-cell therapy in MM?
There is still much to learn about the role of CAR T-cell therapy in MM, especially regarding the best ways to use supportive care and other immune strategies in combination with CARs. This information is needed to ensure that remission times can be prolonged for as long as possible. Investigators are currently working to develop next-generation CARs, also known as “armored CARs,” in which the hope is that the reengineered T-cells will persist in patients for a longer duration.6 The next step in clinical trials will be to use these newer CARs even earlier in the disease course. If and when CAR T-cell therapy gains FDA approval specifically for use in MM, it will be critical to increase patient access to this treatment option. All things considered, it is a very exciting time for CAR T-cell technology in hematologic malignancies, and the hope is that it will also have a role in the treatment of MM.
- Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21832238. Accessed November 6, 2018.
- Zhao Z, Chen Y, Francisco NM, Zhang Y, Wu M. The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm Sin B. 2018;8:539-551. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30109179. Accessed November 6, 2018.
- Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1821. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30147690. Accessed November 6, 2018.
- Rappl G, Riet T, Awerkiew S, et al. The CD3-zeta chimeric antigen receptor overcomes TCR hypo-responsiveness of human terminal late-stage T cells. PLoS One. 2012;7:e30713. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22292024. Accessed November 6, 2018.
- Raje N, Berdeja J, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;37(suppl):abstr 8007. Available at: https://meetinglibrary.asco.org/record/160693/abstract. Accessed November 6, 2018.
- Memorial Sloan Kettering Cancer Center [press release]. MSK scientists build "armored" CAR T cells to smite solid tumors. August 13, 2018. Available at: https://www.mskcc.org/blog/msk-scientists-build-armored-car-cells-smite-solid-tumors. Accessed November 6, 2018.