What's limitations of BCMA (B-Cell maturation antigen) CAR-T Therapy?

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What’s limitations of BCMA (B-Cell maturation antigen) CAR-T Therapy?

What’s limitations of BCMA (B Cell maturation antigen) CAR-T Therapy? B-cell maturation antigen (BCMA) is expressed on plasma cells, making it a major target for highly selective treatment of multiple myeloma.

A phase I study using bb2121 for anti-BCMA CAR T cell therapy in RRMM patients [1] showed that after the third-line treatment, there was an unprecedented 85% remission rate, and 45% of patients achieved complete remission.

In addition, all patients also achieved minimal residual disease (MRD) negative. Before using bb2121, lymphatic removal treatment is required, and fludarabine 30mg/m2 and cyclophosphamide 300mgm2 are used daily for more than 3 days.

The patient’s PFS was 11.8 months (95% confidence interval, 6.2 to 17.8), which is very encouraging in this refractory population. In the extended phase of the trial, 150 x 106 and 450 x 106 doses were selected. Of the 16 patients who received >150 x 106 cells, 16 all achieved MRD negative and 17.7 months of PFS.

What's limitations of BCMA (B-Cell maturation antigen) CAR-T Therapy?

Treatment-related adverse events included hematological toxicity, manifesting as grade 3 or higher neutropenia (85%), leukopenia (58%), and anemia and thrombocytopenia (45%). Cytokine release syndrome (CRS) occurred in 76% of patients, and grade 3 or higher occurred in 6% of patients. The median time to onset of CRS was 2 days (range 1 to 25 days), and the median duration of CRS was 16 days (range 1 to 32 days).

Seven patients received tocilizumab anti-IL6 monoclonal antibody therapy, and four patients received glucocorticoid therapy. The use of tocilizumab and glucocorticoids will not adversely affect the expansion of CAR T cells. 42% of patients had neurotoxicity, mainly grade 1 and 2, and 1 patient had reversible grade 4 neurotoxicity.

There are other BCMA CAR T cell therapies under investigation. The 1b/2 phase study (CARTITUDE-1) of JNJ-4528 was recently reported [2]. The CAR is structurally different from the CD3 and 4-1BB co-stimulatory domains, in which two BCMA-targeted single-domain antibodies are designed to impart affinity. The study demonstrated a 100% response rate (69% complete response or better) and a high MRD negative rate. Based on the phase Ib results, the recommended phase 2 dose of 0.75×106 CAR T cells was selected, which is currently under investigation.

The most common adverse event in 93% of patients included CRS, most of which were grade 1-2 (86%). One patient experienced grade 3 CRS, and one patient died of complications of grade 5 CRS. The median time to onset of CRS was 7 days (range 2-12), and the median duration of CRS was 4 days (range 1-60). 76% of patients used tocilizumab and 21% of patients used corticosteroids. Neurotoxicity occurred in 10% of patients, and only 3% of patients had neurotoxicity of grade 3 or higher. Hematological toxicities above grade 3 include neutropenia (93%), anemia (55%), and thrombocytopenia (69%).

The promising results of anti-BCMA CAR T cell therapy have its own set of challenges. Mainly are the following two aspects:

1. Treatment of drug resistance

The underlying mechanism of treatment resistance remains largely unclear, but involves tumor heterogeneity and antigen escape [3].

BMCA that is heterogeneously expressed at the intratumoral level can lead to preferential targeting of cells with high BCMA while retaining those with low/zero BCMA expression, leading to the growth of clones of the latter. In fact, BCMA often loses expression when the disease relapses after the first CAR T infusion, which indicates that CAR T cells have selected BCMA-negative MM clones [4].

For BCMA antigen escape, one of the most detailed methods is the error physiology of BCMA antigen. BCMA can inadvertently transfer from a tumor to T cells in a process called phagocytosis, causing T cell death or it can flow into the blood circulation (now called serum BCMA (sBCMA)), which is mediated by γ-secretase. Both will lead to inhibition of tumor cell recognition [5]. Although lower sBCMA levels are indeed associated with good ORR [6], it is not always associated with CART dose response, and its expression is still very low at relapses with increased disease burden, indicating that the resistance mechanism can prolong in addition to tumors. Internal factors.

Related to this, a recent study using longitudinal single-cell transcriptomics and extensive genomic analysis emphasized molecular BCMA aberrations. They found that the patient’s resistance to bb2121 was related to biallelic loss of BCMA. Most MM cells show a loss of heterozygous chr16p, including the BCMA locus, accompanied by nonsense mutations of other alleles, resulting in biallelic inactivation of BCMA [5].

This was confirmed by another study, which revealed that genome instability is related to biallelic deletion of the BCMA locus after CAR T cell infusion. Both alleles were intact before CAR T treatment. Therefore, this indicates that branching evolution occurred during the treatment process and that MM cells acquired genomic abnormalities when selecting BMCA-negative cells.

2. Toxicity

After CAR T cells are activated, cytokine release syndrome (CRS) and neurotoxicity mediated by pro-inflammatory cytokines are another long-standing problem. CRS manifests as fever, nausea, and flu in mild cases, but may escalate to hypotension, cardiac arrest, and liver failure in severe cases. On the other hand, neurotoxicity can range from mild confusion and delirium to severe dullness, seizures, and white matter degeneration.

Although it is a plasma cell marker, BCMA is also co-expressed on normal B lymphocytes. Therefore, BCMA CAR T cell therapy may also introduce targeted/non-tumor effects. Common manifestations include B cell hypoplasia and neutropenia Symptoms and immunosuppression that lead to an increased risk of infection.

In the same analysis as above, the average incidence of CRS and neurotoxicity reported were 80.3% and 10.5%, respectively [7]. Although toxicity is a common event, the patient’s toxicity-related fatality rate is controllable. A high degree of toxicity is more commonly observed in patients with heavier tumor burden or higher CAR T cell doses [8]. Off-the-shelf drugs are often used to control toxicity, such as IL6R antagonists (tocilizumab) for CRS and corticosteroids for neurological symptoms.

(source:internet, reference only)

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