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On 14 February 2019, Alfred Garfall from the Perelman School of Medicine, University of Pennsylvania, PA, USA, presented at the 1st European CAR T Cell Meeting in Paris, France, on the topic of chimeric antigen receptor T-cell (CAR T) therapy in multiple myeloma (MM). Dr Garfall summarized the latest clinical data, the main downfalls of CAR T therapy in the MM setting and mechanisms of improving efficacy for future constructs and trials. Here, the MM Hub present the main topics from his talk.1
Immunotherapy is a rapidly evolving field in MM with many potential cell surface targets already identified such as B-cell maturation antigen (BCMA) and CS1 (SLAMF7). Some of these have already been utilized to create clinically targeted licensed therapies such as daratumumab, which is a monoclonal antibody (MAb) targeting CD38.
Whilst the use of CAR T therapy in MM is not currently licensed, there are several ongoing clinical trials, with many more in the pipeline, creating a crowded market. Most CAR T therapies in clinical trials in MM target BCMA, but other trials are currently investigating CS1 (SLAMF7), CD38, CD138, NKG2D ligands, Lewis Y antigen and surface immunogloblulin as potential targets. During ASH 2018, 15 clinical trials targeting BCMA in MM were presented, 13 of which were CAR therapies, which is an incredible number for just one target and therapeutic approach.
There are three main anti-BCMA CAR T phase I trials in MM; the latest data for each is listed here:
Whilst these three CARs all target BCMA and have the most mature data available, there are differences in their design including the lymphodepletion regimen, the pretreatment disease burden, and the need for documented BCMA expression.
All the studies listed above enrolled heavily pretreated patients including those with high-risk cytogenetics. The ORRs therefore are very impressive, considering the population treated. There were also reasonable toxicities in terms of CRS and neurologic events, which was expected given that BCMA is only expressed on a subset of B cells and mature plasma cells, minimizing the off-target effect.
In anti-CD19 CAR T therapies, which are licensed for the treatment of diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), the response rates flatten over time indicating that late relapses are relatively rare.
However, in CAR T trials in MM to date, this is not the case. In the Bluebird study, a median progression free survival (PFS) of 17.7 months was seen in patients who were minimal-residual disease (MRD) negative. Whilst this is a significant result in such a heavily pretreated population, it is indicative of the fact that even the patients who have responded best to treatment relapse over time.1 This was also experienced in the NCI trial whereby patients experienced disease progression over time, following CAR T therapy.5
So far, clinical trials with anti-BCMA CAR T therapy have shown that BCMA is a valid target for myeloma immunotherapy and that the approach of CAR T is applicable in targets aside from CD19 in the lymphoma setting. Anti-BCMA CAR T can elicit significant responses in the heavily pretreated relapsed/refractory (RR) population, but most patients relapse despite a clinically significant PFS. The cytotoxicity profile is reasonable, with no significant effects on normal tissues, and is in-line with the expected effects from the anti-CD19 experience.
To understand why there is a loss of response, there are two main questions:
1. Are the CAR T cells persisting?
2. Are the CAR T cells active?
1. Provide CAR T during an earlier line of therapy
2. Co-target other antigens (CD19)
A new study (NCT03549442), utilizing both strategies listed above (treating with CAR T earlier in the pathway and co-targeting CD19), is currently recruiting patients with high-risk MM. Patients will receive standard first-line therapy and, following a stable response, will have their T cells and stem cells (if transplant eligible) harvested. The initial therapy is then consolidated with either anti-BCMA CAR T therapy or anti-BCMA and anti-CD19 CAR T therapy. Results from a similar study were recently published by Shi et al. at ASH 2018 with promising results providing justification for this approach.8
3. Increase the potency of the CAR T cells. This can be done in a manner of ways, including;
4. Increase BCMA expression on the cell surface
5. Target multiple plasma cell antigens on the myeloma cell surface
The immunotherapy field in MM is crowded, especially in comparison to the DLBCL and ALL fields, with many bispecific antibodies targeting BCMA, CD38, and GPRC5D, and antibody-drug conjugates targeting BCMA are also providing promising data.
Therefore, it is currently unknown whether any of these methods or strategies targeting BCMA or other MM immunotherapy targets may preclude another and how they will be utilized. A clinical benefit may be provided in using these in combination or in sequence.
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