Abecma has just been approved for listing, BMS/Bluebird issued a paper explaining the mechanism of BCMA CAR-T resistance

In March 2021, the CAR-T cell product Abecma (idecabtagene vicleucel; ide-cel) jointly developed by Bristol-Myers Squibb (BMS) and bluebird bio, with BCMA as the target, was approved by the US FDA to treat relapse or Drug-resistant multiple myeloma has become the fifth CAR-T product to be marketed in the world.

Like all anti-tumor drugs, BCMA CAR-T also has drug resistance issues.

Recently, BMS, Bluebird, and Dana Farber Cancer Institute (Dana Farber Cancer Institute) jointly published an article in Nature Communications, explaining a resistance mechanism of BCMA CAR-T: BCMA biallelic loss.

Research summary BCMA CAR-T cell therapy showed a profound and long-lasting response to multiple myeloma.

However, it often relapses after treatment, and the mechanism of resistance is still unclear.

Scientists performed single-cell genome characterization on longitudinal samples of patients who relapsed and lacked response after initial CAR-T cell treatment, and found that the biallelic loss of BCMA was lost.

This loss leads to a lack of proliferation of CAR-T cells after the second infusion, and is reflected in the lack of soluble BCMA in the patient's serum.

The author’s findings suggest that the detection of BCMA gene mutations in multiple myeloma cells that relapse after BCMA CAR-T cell therapy is the basis for finding drug-resistant treatment options.

Patient profile The patient received four-line treatment before CAR-T cell therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 antibodies, but the response was limited.

The patient was recruited for the BCMA CAR-T phase trial (NCT02658929).
On day 0, after fludarabine (30mg/m2/day) and cyclophosphamide (300mg/m2/day), they received a dose of 150×10^6 CAR-T cell therapy.

Partial response was reached after 3 months and relapsed after 9 months.

The same program was used for the second time, but the CAR-T dose was increased to 450×10^6, and there was no response.

Sample collection Samples were collected at 8 time points for single-cell sequencing.

BCMA CAR-T depletion marker expression sequencing results showed early and late depletion markers CD274 (PD-L1), PDCD1 (PD-1), LAG3, TIGIT, starting 2 weeks after the first CAR-T cell infusion Gradually increase.

The patient's serum sBCMA drops to detect the soluble BCMA (sBCMA) level (mainly produced by multiple myeloma cells) in the patient's serum at different time points.

It was found that a high level was observed before the first CAR-T cell infusion, and the level dropped significantly to a very low level consistent with clinical response; however, even when recurrence and multiple myeloma (MM) load increased, sBCMA It is still very low, which indicates that MM cells lack BCMA production.

BCMA biallelic loss single-cell transcriptome analysis determined that in three samples (at relapse and after the second CART cell infusion), most MM cells lacked 16p, including the BCMA site located on 16p13.
13.

The purified CD138 cells collected 2 weeks after the second CAR-T infusion were subjected to deep whole exome sequencing (WES) to further verify these findings.

It is worth noting that the copy number changes detected by WES almost completely overlap with single-cell RNA sequencing (sRNA sequence), including the deletion of 16p.

The editor concluded that BCMA CAR-T has made great progress in the treatment of multiple myeloma, so BMS and Bluebird's Abecma (idecabtagene vicleucel; ide-cel) were approved by the FDA.

But similar to other cancer treatment drugs, drug resistance is a problem that must be faced.

BMS/Bluebird and Dana Farber Cancer Institute carefully studied a case of recurrence after BCMA CAR-T treatment by means of single-cell sequencing and the increased dose treatment did not respond here, showing that multiple myeloma passed BCMA biallelic Mutations lead to the loss of therapeutic targets and induce functional exhaustion of BCMA CAR-T, resulting in ineffective treatment.

A few days ago, Legend Biology and its collaborator Yang Sen filed a rolling application for a biological product license in the United States.
Keji Biology’s BCMA CAR-T was previously recognized as a breakthrough therapy and will soon enter the clinic in the future.

The drug resistance cases of BMS and Bluebird products are a good reference for the future clinical use of related products at home and abroad.

References 1.
Mehmet Kemal Samur et al, Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma, NATURE COMMUNICATIONS | (2021) 12:868 | https://doi.
org/10.
1038/ s41467-021-21177-52.
and-bluebird-bio%E2%80%99s-Abecma-idecabtagene-vicleucel-the-First-Anti-BCMA-CAR-T-Cell-Therapy-for-Relapsed-or-Refractory-Multiple-Myeloma share it.

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