FDA Fast Tracks CB-011 for Relapsed/Refractory Multiple Myeloma

The FDA has granted a fast track designation to CB-011, a CRISPR-edited allogeneic CAR T-cell therapy developed by Caribou Biosciences, for the treatment of patients with relapsed/refractory multiple myeloma.¹

CB-011 targets the B-cell maturation antigen (BCMA). This is the first allogeneic anti-BCMA CAR-T cell therapy engineered to improve duration of antitumor response through an immune cloaking, genome-editing approach that removes the B2M protein and inserts a B2M–HLA-E fusion protein, according to the company.²

In November 2022, the FDA cleared an Investigational New Drug application for CB-011.2 Now, the product is under evaluation in the multicenter, open-label study CaMMouflage trial (NCT05722418).^3,4

“Fast Track designation for CB-011 allows us instrumental interactions with the FDA as we progress our clinical development and regulatory plans for CB-011,” Syed Rizvi, MD, chief medical officer at Caribou Biosciences, stated in a press release.¹ “This designation could not be [timelier,] as we recently dosed our first patient in the phase 1 CaMMouflage trial.”

The CaMMouflage trial will include patients who have received at least 3 prior lines of therapy. Eligible patients are also required to have an ECOG performance status of 0 or 1 and to have adequate hematologic, renal, hepatic, pulmonary, and cardiac function.³

Patients who have received a BCMA-targeted therapy within 3 months of enrollment and/or any prior CAR-T cell therapy are excluded. Those who received autologous stem cell transplant within 6 weeks of lymphodepletion or allogeneic stem cell transplant within 6 months of lymphodepletion, who have an active or prior history of central nervous system involvement, or who have received a live, attenuated vaccine with 4 weeks of lymphodepletion are not eligible.³

In the part A, the escalation stage of the trial, investigators will assess ascending doses of CB-011 in combination with cyclophosphamide and fludarabine to establish the recommended phase 2 dose (RP2D) of the regimen in a standard 3+3 dose-escalation design. For part B, the expansion stage, investigators will assess responses to the RP2D, or the maximum tolerated dose as measured by International Myeloma Working Group criteria.³

Recruitment for CaMMouflage is ongoing. Caribou shared plans to assign patients to a single administration of CB-011 at a dose of 50 x 10⁶ CAR-T cells this year.¹

Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology was utilized to make 4 gene edits in the creation of CB-011. In edits 1 and 2, investigators target cancer cells by site-specifically inserting a humanized anti-BCMA CAR into the TRAC gene. This mechanism knocks out T cell receptor expression, thereby reducing the risk for graft-vs-host disease (GVHD).²

In edits 3 and 4, investigators prevent recognition and rejection by patient T cells and blunt rejection by natural killer (NK) cells by site-specifically inserting a B2M–HLA-E peptide fusion gene into the B2M gene of the CAR T cells. These edits disable endogenous B2M expression, which eliminates endogenous HLA class I presentation and reduces T cell-mediated rejection. At the same time, these changes facilitate expression of B2M–HLA-E which reduces rejection caused by NK cells.²

Prior preclinical findings presented at the 2022 AACR Annual Meeting indicated that the CAR T cells expressing the B2M-HLA-E fusion induced a survival benefit compared with cells that do not express the fusion in the presence of NK cells in vitro.⁴ This result suggests that these cells may be able to fight off a recipient’s NK cells and circulate longer.

Furthermore, CB-011 induced long-term survival in mice carrying established orthotopically-engrafted multiple myeloma cells. Mice who received high doses of CB-011 also appeared to avoid GVHD.⁴

“Our goal is to develop CB-011 as a readily available off-the-shelf treatment option for patients with relapsed or refractory multiple myeloma to overcome the need for apheresis or bridging therapy, variable quality and long manufacturing timelines, manufacturing failures, or the inability to bear the burden of treatments that require frequent dosing over several months,” Rizvi added in the press release.¹

CB-011 is Caribou’s second allogeneic CAR-T cell agent that is under exploration in hematologic malignancies.

Investigators are assessing CB-010, a CAR-T cell therapy with a PD-1 knockout, in patients with relapsed or refractory B cell non-Hodgkin lymphoma as part of the ongoing phase 1 ANTLER trial NCT04637763).² One patient in that trial who received 8 prior lines of systemic therapy had an ongoing complete response through month 15.⁵

References

1. Caribou Biosciences announces FDA granted fast track designation to CB-011, an allogeneic CAR-T cell therapy for relapsed or refractory multiple myeloma. News release. Caribou Biosciences. April 4, 2023. Accessed April 6, 2023. https://investor.cariboubio.com/
2. Caribou Biosciences announces FDA clearance of IND application for CB-011, an allogeneic anti-BCMA CAR-T Cell therapy for the treatment of relapsed or refractory multiple myeloma. News release. Caribou Biosciences. November 21, 2022. Accessed April 6, 2023. https://investor.cariboubio.com/news-releases/
3. CRISPR-edited allogeneic anti-BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma (CaMMouflage). Updated March 2, 10, 2023. Accessed April 6, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05722418
4. Garner E, Degagne E, Roy S, et al. A BCMA-specific allogeneic CAR-T cell therapy (CB-011) genome-engineered to express an HLA-E fusion transgene to prevent immune cell rejection. Cancer Res. 2022;82(suppl 12):LB009. doi:10.1158/1538-7445.AM2022-LB009
5. CRISPR-edited allogeneic anti-CD19 CAR-t cell therapy with PD-1 knockout induces prolonged complete response in relapsed/refractory follicular lymphoma patient: case report from CB-010 ANTLER trial. Presented at: the Lymphoma, Leukemia, & Myeloma Congress; New York, NY; October 18-22, 2022.