Cancer Discov: CAR-T cell therapy that overexpresses BCL-2, the efficacy of "anti-cancer weapon" is further improved!

Since the first CAR-T cell therapy was launched in 2017, the era of cell therapy has officially begun, and it has achieved good clinical results in a variety of tumor treatments, and B-cell lymphoma is one
of them.

Recently, a research team from the University of Pennsylvania launched an exploration of the anti-tumor effect of CAR-T therapy, and they found that the anti-apoptotic protein BCL-2 inhibitor can have a synergistic effect with CAR-T therapy, which in turn has a more effective therapeutic effect on B-cell lymphoma (the lethality of CAR-T treatment alone is 47%-63%, while the lethality of BCL-2 inhibitors and CAR-T on tumors is 75%-88%)
。 At the same time, they also designed and manufactured CAR-T cells that overexpressed BCL-2 or BCL-2 (F104L) mutations, and found that overexpression of BCL-2 can not only improve the resistance of CAR-T cells to BCL-2 inhibitor toxicity, but also enhance their anti-tumor ability
。 The research results were published in the authoritative journal Cancer Discovery under the title of "Modulation of BCL-2 in both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T cell Immunotherapy against Cancer"
.

Figure 1 Research results (Source: [1])

In this study, the researchers conducted targeted screening of 29 pro-apoptotic drugs in the B-cell precursor leukemia cell line (NALM6), and they found that BCL-2 inhibitors are toxic enhancers of CAR-T cell therapy and can significantly improve the tumor killing function
of CAR-T cells 。 Among them, the FDA-approved drug venetoclax has the strongest effect on improving the tumor killing ability of CAR-T cells, with CAR-T alone having a lethality of 47%-63% on tumors, while BCL-2 inhibitors combined with CAR-T have a lethality of tumors in 75%-88%[1].

To investigate whether administration enhances CAR-T cell-mediated tumor killing capabilities, the researchers used two different B-cell lymphoma cell lines and one leukemia cell line, OCI-Ly18, which have different sensitivities
to venetoclax.

Fig.

By comparing the transcriptome of animal tumor cells receiving CAR-T and receiving CAR-T/venetoclax combination therapy, the study data show that combination therapy enhances CAR-T-mediated tumor killing ability
by promoting apoptosis of tumor cells and inhibiting cancer cell cycles.

In experiments, the researchers found that the use of high doses of venetoclax leads to toxicity to CAR-T cells, resulting in a continuous decline in the anti-tumor ability of CAR-T cells until it disappears
。 To change this, the researchers designed CAR-T cells that overexpressed BCL-2 or BCL-2 (F104L) mutations to modulate the tolerance of CAR-T cells to venetoclax, and the results showed that CAR-T cells that overexpressed BCL-2 or BCL-2 (F104L) mutations were more resistant to venetoclax-induced cytotoxicity
than CAR-T cells.

In the absence of venetoclax, CAR-T cells that have expressed BCL-2 alone can produce stronger tumor killing effects than conventional CAR-T cells, but the effect is not as obvious
as the combination of venetoclax and CAR-T.

Fig.

To figure out the mechanisms by which BCL-2 overexpression may increase the antitumor activity of CAR-T cells, the researchers conducted functional studies
of CAR-T cells in vitro and in vivo.

In addition, the researchers say that although BCL-2 overexpression has led to a significant increase in the anti-lymphoma activity of CAR-T cells, the key issue with this approach is its long-term safety
.

In summary, the researchers proposed and confirmed a new therapeutic idea
of improving the anti-tumor effect of CAR-T cells by modulating the BCL-2 signaling pathway of CAR-T cells and tumor cells.

Resources:

[1] Lee YG, Guruprasad P, Ghilardi G, et al.