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Exploring New Paths for CAR T-Cell Therapy Research in Multiple Myeloma

Melissa Alsina, MD, gave a talk on novel CAR therapies, targets, and approaches at the 2022 ASCO meeting.

Although great strides have been made in treating multiple myeloma (MM) with chimeric antigen receptor (CAR) T-cell therapies, there is still work to be done in improving response rates, duration of response (DOR), and survival rates.

Melissa Alsina, MD, associate professor of medicine, Blood and Marrow Transplant Program, and head,Multiple Myeloma Transplant Program, Moffitt Cancer Center, gave a presentation titled “The road not yet taken: Novel CARs and newer horizons” that explored where improvements could be made in the CAR T process at the 2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, held both virtually and in Chicago, Illinois.1

"The main target that we have been using for myeloma CAR Ts is BCMA because it’s essentially exclusively expressed in the myeloma cells. We have 2 CAR Ts that have been approved within 1 year for multiple myeloma: idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb) and ciltacabtagene autoleucel (cilta-cel; Carvykti; Legend Biotech)... Even though these CAR Ts are very effective for this patient population, there’s still a lot of work to do because the majority of these patients do relapse after these treatments,” Alsina said during her presentation.

Alsina first discussed a poster presented by Doris Hansen, MD, Assistant Member, Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center on a real-world experiencestudy conducted at Moffitt evaluating ide-cel.2 Investigators found that the best overall response rate (ORR) was 86%, complete response (CR) rate was 42%, 78% minimal residual disease (MRD)-negative, very good partial response (VGPR) rate was 21%, and PR rate was 23%. The median progression free survival (PFS) was 10.3 months (95% CI, 10.1-NE and the 6-month overall survival (OS) estimate was 92% (95% CI, 87-97).

READ MORE: Cilta-Cel Shows Promise in Earlier Lines of Treatment in Patients With Progressive Multiple Myeloma

Of all the patients included in the study, 77% would not have been eligible for the pivotal KarMMa study (NCT03361748). Hansen and colleagues also evaluated responses according to prior anti-BCMA therapy and found that median PFS in this group was 5.8 months (95% CI, 3-NR) and median OS was 7.3 months (95% CI, 7.36-NR). Patients that had prior bispecific T cell engager (BiTE) therapy had a median PFS of only 2.7 months (95% CI, 1.9-NR).

Alsina listed areas in which CAR T-cell therapies could be improved: manufacturing, in which one could change the process, target, or substrate; lymphodepletion, to enhance the target or induce CAR T-cell persistence; or maintenance, to enhance immune effect or direct myeloma cell death.1

She discussed other studies presented at ASCO, including a study (NCT04155749) presented by Matthew J. Frigault, MD, of Massachusetts General Hospital Cancer Center that showed that CART-ddBCMA cells made with a synthetic peptide for better binding to myeloma cells yielded a 100% ORR in study participants.3 A study (NCT05016778) presented by He Huang, MD, of Zhejiang University showed that GPRC5D-targeted CAR T-cells (OriCAR-017) also yielded a 100% ORR in study participants.4 A third study presented by Huan Du, MD, PhD, of Changzheng Hospital evaluated GC012F, a BCMA/CD19 dual-targeted CAR T-cell therapy, for an ORR of 89%.5

Alsina also discussed the potential of allogeneic CAR T-cell therapies, γδ T cells, and PI3K inhibitors such as bb007 which was used in the 2seventy bio program, bb21217. 2seventy announced in January 2022 that they would not be pursuing further development of bb21217, despite observing a median DOR of about 2 years in study participants.6

In the lymphodepletion phase, Alsina discussed the potential of interleukin-7 and γ-secretase inhibitors, and a preclinical study that showed that γ-secretase enhanced BCMA expression and improved survival after CAR-T in MM cells in mouse models.1

In terms of maintenance, Alsina discussed immunomodulatory drugs, BCMA antibody drug conjugates, cd38 antibodies, and bispecific antibodies. Many studies are exploring moving CAR T therapy to earlier lines of therapy, including a study evaluating ide-cel in different combinations of therapy in early treatment (NCT04855136). On the other hand, Moffitt has also started to explore the use of CAR T-cell therapy after a prior CAR T-cell therapy with the same target, such as ide-cel after cilta-cel treatment. Alsina said that not much data has been generated yet but that median PFS has not been reached and it may be a valid option.

“In summary, we have multiple opportunities for improvement, in terms of manufacturing, lymphodepletion, or maintenance. I think there’s a lot of work to be done but it’s very promising and it’s likely to improve the results we have seen so far,” Alsina concluded.

To read more coverage of ASCO 2022, click here.

REFERENCES
1. Alsina M. The road not yet taken: Novel CARS and newer horizons. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022.
2. Hansen DK, Sidana S, Peres L, et al. Idecabtagenevicleucel (Ide-cel) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): Real-world experience. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Poster #466.
3. Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract # 8003.
4. Huang H, Hu Y, Zhang M, et al. Phase I open-label single arm study of GPRC5D CAR T-cells (OriCAR-017) in patients with relapsed/refractory multiple myeloma (POLARIS). Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract # 8004.
5. Du J, Jiang H, Dong B, et al. Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract # 8005.
6. 2seventy bio shares key milestones and business updates for 2022. News release. 2seventy bio. January 11, 2022. Accessed June 5, 2022. https://www.businesswire.com/news/home/20220111005551/en