Anti-BCMA CAR T Cell Development Continues to Evolve for Multiple Myeloma

Each of the many BCMA-targeted chimeric antigen receptor (CAR) T cells in development demonstrate a different efficacy and safety profile, and each have different constructs. None of the agents have reached the FDA yet, but data for many of the agents were presented at the 2018 ASH Annual Meeting.

Showing promising data in the phase I CRB-401 trial, bb2121 is at the front of the race for BCMA development.¹Additionally, LCAR-B38M, has also shown strong phase I results.²A number of oral abstract sessions at the ASH meeting highlighted other therapies, including MCARH171,³JCARH125,⁴P-BCMA-101,⁵FCARH143,⁶bb21217,⁷CT053,⁸and a yet unnamed therapy from HRAIN Biotechnology in China (BCMA-CART).⁹

Proliferation of CAR T cell Candidates

Four agents currently being explored in the United States provide a look at findings across different CAR T cell constructs, these agents are MCARH171, JCARH125, FCARH143, and P-BCMA-101.

MCARH171 is transduced with a retrovirus, with no predefined CD4:CD8 ratio. The treatment has a CD8 alpha hinge and a 4-1BB costimulatory domain.³JCARH125 and FCARH143 are similar, as both agents are manufactured from cells with a predefined CD4:CD8 ratio, both have 4-1BB costimulatory domains and fully human BCMA single-chain variable fragment (scFv), and both are transduced with a lentivirus vector.^4,6

P-BCMA-101 is manufactured using the piggyback approach, which is a non-viral system for DNA delivery.⁵The agent uses a small human fibronectin domain for BCMA. In preclinical work, the design of the molecule resulted in higher T stem cell memory T cells (T_SCM), according to senior investigator Krina Patel, MD MSc. "We believe T_SCMcells in this product are the key to increase duration of response and reduce toxicity," she said.

In a phase I study,⁵21 patients with multiple myeloma received P-BCMA-101 across 5 dose levels. At the highest dose (n = 3), the objective response rate (ORR) was 100%, with a very good partial response (VGPR) or better rate of 68%. At lower doses, the response rate was near 70%. Across doses, only 9.5% of patients experienced cytokine release syndrome (CRS), which was grade 1/2 in severity. There were no high-grade events.

Patel, from the MD Anderson Cancer Center, noted that enrollment in the study is continuing and that a pivotal study is being initiated. Based on the expected timelines, she anticipated that a biologics licensing application could be submitted for P-BCMA-101 in 2020.

"P-BCMA-101 at all doses induces high response rates and deep responses in a heavily pretreated relapsed/refractory multiple myeloma population, with responses still developing," she said. "Lack of significant toxicity may allow for greater patient access, such as through administration at community hospitals and/or outpatient sites."

Initial proof of concept findings for JCARH125 and final results for MCARH171 were both presented by Sham Mailankody, MBBS, at the ASH Annual Meeting and data for FCARH143 were presented by Damian J. Green, MD, with varying results seen across studies.

In the phase I/II EVOLVE study,⁴44 patients received various doses of JCARH125, with an ORR of 82%. The rate of VGPR or better was 48% and the complete remission (CR) or stringent CR (sCR) rate was 27%. Eighty percent of patients had CRS, with 9% having a grade ≥3 event. Neurological adverse events (AE) were experienced by 18% of patients, with 7% having a grade ≥3 event.

"JCARH125 is a BCMA CAR T cell product with a fully human binder and optimized manufacturing process that enriches for central memory T cell phenotype," said Mailankody, from the Myeloma Service at the Memorial Sloan Kettering Cancer Center. "JCARH125 was highly active in a heavily pretreated relapsed/refractory multiple myeloma patient population with limited follow-up so far."

The study exploring MCARH171³enrolled 11 patients at 2 different doses. Overall, 46% had a VGPR and 2 patients had a partial response. No patients had a CR/sCR and the ORR was 64%. Overall, 55% of patients had CRS, and 9% had neurotoxicity. CRS was mostly grade 1/2, with 2 patients (18%) having a grade 3 event. The one neurotoxicity event was grade 2 in severity.

"MCARH171 has an acceptable safety profile and no dose-limiting toxicities reported," said Mailankody. "There was no clear dose-response noted for toxicities, including CRS. There is a dose-response for efficacy with promising responses at dose levels of 450 million cells or more. Peak expansion correlated with durability of response."

Both MCARH171 and JCARH125 were investigated at MSK. Mailankody noted that future research would focus on JCARH125, rather than MCARH171, partially due to the origin of the anti-BCMA scFv used in each agent (human vs murine). Additionally, Mailankody cited the clinical profiles of the agents as a key factor in the decision to focus on JCARH125.

"Results support the development of human-derived BCMA-targeted CAR T-cell therapy for myeloma," he said. "JCARH125, a human derived BCMA-targeted CAR T-cell therapy stemming from work at MSKCC, currently is in a multicenter phase I/II trial."

FCARH143 was examined in a phase I study⁶at 2 doses across 11 patients, each having different BCMA expression levels. All patients experienced a response, with a CR/sCR rate of 36% and a VGPR rate of 46%. CRS was experienced by 91% of patients, although no events were grade ≥3 in severity. There was 1 case of neurotoxicity, and no dose-limiting toxicity was seen.

"FCARH143 BCMA CAR T cells are well tolerated, and initial responses are promising in heavily pretreated/high-risk multiple myeloma," said Green, from the Department of Medicine at the University of Washington, Seattle, Washington. "Factors contributing to both CAR T cell persistence and disease relapse require further elucidation."

Two patients, 1 with low BCMA expression and 1 with high, experienced relapse after 79 and 180 days, respectively. Both patients were treated with a lower dose of 150 x 10⁶CAR+ T cells. Antigen loss was identified as a potential mechanism of resistance.

"BCMA antigen loss may represent 1 mechanism of resistance," Green noted. "Measures that increase BCMA expression may broaden eligibility and improve responses."

Enhancing a Frontrunner

Up to this point, bb2121 had shown the most promise and the greatest potential for reaching the FDA. The treatment received a breakthrough therapy designation from the agency in 2017 and has also been granted PRIME eligibility from the EMA. This agent has a 4-1BB costimulatory signaling domain, with a murine scFv for BCMA.¹

Updated findings from the CRB-401 trial were presented at the 2018 ASCO Annual Meeting¹with 194 days of follow-up for the pivotal dose. In this update, the CR/sCR rate was 50% with bb2121, and 36.4% of patients had a VGPR. Overall, bb2121 demonstrated a median progression-free survival (PFS) of 11.8 months and a median duration of response of 10.8 months.

At the ASH meeting,⁷initial results were presented for bb21217, which is built using the bb2121 construct. In the bb21217 manufacturing process, bb2121 is cultured with the PI3 kinase inhibitor bb007, to enrich for T cells with a memory-like phenotype. Cells of this phenotype are thought to persist and function longer than non-enriched CAR T cells, according to lead investigator Nina Shah, MD.

"CAR T cells manufactured with and without bb007 eliminate tumors in established multiple myeloma xenografts equally well," Shah said. "However, opposite flank tumor rechallenge resulted in no tumor growth in mice treated with bb007 cultured CAR T cells, suggesting longer persistence of anti-tumor effect."

In preliminary results from the phase I CRB-402 study,⁷the CR/sCR was 25%. Fifty percent of patients had a VGPR and the ORR was 83.3%. All-grade CRS occurred in 67% of patients, most of which was grade 1 or 2 in severity. One patient had grade 3 CRS and no patients had a grade 4 event. Neurotoxicity occurred in 25% of patients.

Chinese Therapies Show Intriguing Results

The lead agent developed in China, LCAR-B38M, may soon enter US markets, following a licensing agreement between the developer Legend Biotech and Janssen Biotech. Globally, the therapy is being developed as JNJ-68284528 in a phase Ib/II clinical trial for patients with multiple myeloma (NCT03548207).²

JNJ-68284528/LCAR-B38M consists of 2 BCMA targeting domains made from variable fragments of llama heavy-chain antibodies. The costimulatory domain is 4-1BB and the agent is transduced with a lentivirus vector.²

The study enrolled 74 patients, with findings from 57 presented at ASH.²The ORR was 88%, with a 74% CR/sCR rate and a 3% VGPR rate by IMWG response criteria. The median duration of response was 16 months and the median PFS was 15 months. The median overall survival (OS) was not yet reached, with a 12-month OS rate of 75%. CRS occurred in 90% of patients, with grade 3 events in 7%. Grade 4 CRS did not occur. Grade 1 neurotoxicity was experienced by 1 patient.

"LCAR-B38M displayed a safety profile consistent with BCMA-targeted CAR T-cell therapy. CRS was mostly grade 1 and 2 and the median onset of CRS was 9 days," said lead investigator Wan-Hong Zhao, MD, PhD, Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi, China. "Response was achieved with low CAR+ T cell doses. BCMA expression did not correlate with clinical response."

Another CAR T-cell therapy being developed in China, CT053, consists of a human anti-BCMA scFv along with a 4-1BB costimulatory domain.⁸This agent was specifically designed with the hope of increasing tolerability, lead investigator Songfu Jiang, MD, said during his presentation.

The study included 21 patients, of which 17 received treatment and 14 were available for efficacy assessment in July 2018.⁸The ORR with CT053 was 100%, which consisted of a CR/sCR rate of 35.7% and a VGPR rate of 42.9%. CRS occurred in 29% of patients. There were 4 patients with a grade 2 event and 1 with a grade 3 event. There was no neurotoxicity reported.

"BCMA-targeted CAR-T cell therapy emerges as promising treatment for patients with relapse/refractory multiple myeloma," said Jiang, from the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. "CT053 CAR BCMA T cells conferred tolerable safety profiles and sufficient CAR T-cell expansion and persistence was observed."

Another new CAR T-cell therapy being developed in China, known currently as BCMA-CART, more closely resembles MCARH171. For this therapy, an anti-BCMA scFv is transduced with a retrovirus vector. The agent has a 4-1BB costimulatory domain.⁹

A study exploring BCMA-CART enrolled 20 patients across 3 hospital.⁹The study was intended to provide a therapy to patients with very little remaining treatment options, according to lead investigator Yarong Liu, PhD. As such, patients with ECOG performance status of 3 and 4 were allowed to enroll.

At the analysis,⁹the ORR was 85%, which included a VGPR rate of 25% and a CR/sCR rate of 40%. Similar responses were seen regardless of ECOG status. The median PFS was 15.0 months and the 22-month PFS rate was 45%. Median OS was not reached, and the 22-month OS rate was 79%. CRS was experienced by 45% of patients, with grade 3 CRS in 5% of patients.

"BCMA-CAR T cells had promising efficacy with the infused dose, with only mild and manageable CRS for relapsed/refractory multiple myeloma patients. No neurotoxicity was observed, only 1 patient had grade 3 CRS," said Liu, from HRAIN Biotechnology. "CAR-T cells expand and persist long in patients and also expand well. They did persist in patients with progressive disease, but these patients had ECOG greater than 3."

Other BCMA Approaches Provide Competition

In addition to traditional CAR T-cell therapies targeting BCMA, a variety of other approaches are currently under exploration include "off the shelf" allogeneic cell therapies, bispecific T cell engager cells, and antibody-drug conjugates. Efficacy data for these approaches have been comparable with findings for the CAR T-cell therapies. As each approach continues to advance, adverse events and costs may become a deciding factor.

References:

1. Raje NS, Berdeja JG, 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;36 (suppl; abstr 8007).
2. Zhao W-H, Liu J, Wang B-Y, et al. Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 955.
3. Mailankody S, Ghosh A, Staehr M, et al. Clinical Responses and Pharmacokinetics of MCARH171, a Human-Derived Bcma Targeted CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Final Results of a Phase I Clinical Trial. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 959.
4. Mailankody S, Htut M, Lee KP, et al. JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE). Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 957.
5. Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapse/refractory (r/r) multiple myeloma (MM). Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 1012.
6. Green DJ, Pon M, Sather BD, et al. Fully Human Bcma Targeted Chimeric Antigen Receptor T Cells Administered in a Defined Composition Demonstrate Potency at Low Doses in Advanced Stage High Risk Multiple Myeloma. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 1011.
7. Shah N, Alsina M, Siegel DS, et al. Initial Results from a Phase 1 Clinical Study of bb21217, a Next-Generation Anti Bcma CAR T Therapy. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego. Abstract 488.
8. Jiang S, Jin J, Hao S, et al. Low Dose of Human scFv-Derived BCMA-Targeted CAR-T Cells Achieved Fast Response and High Complete Remission in Patients with Relapsed/Refractory Multiple Myeloma. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 960.
9. Liu Y, Chen Z, Fang H, et al. Durable Remission Achieved from Bcma-Directed CAR-T Therapy Against Relapsed or Refractory Multiple Myeloma. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 956.