The next generation of chimeric antigen receptor (CAR) T-cell (CAR-T) therapies for solid tumors may be CAR-less, “bionic,” and armed with a bispecific antibody. Early preclinical data reported at the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019, showed that these bionic T cells appear to have cytotoxic activity.
To create the engineered T cells, constructs were used that lacked CAR but had 1 of the following costimulatory domains: FLAG-4-1BB-ζ, FLAG-CD28-ζ, FLAG-ICOS-ζ, FLAG-OX40-ζ, and FLAG-27-ζ. To serve as a control, a batch of T cells were transduced with constructs that lack the costimulatory domain-FLAG-ζ.
The ability of the bionic T cells to survive in hypoxic conditions varied depending on costimulatory endodomain. For instance, 61% of bionic T cells with costimulatory domain CD28-ζ died in hypoxic conditions compared with only 15% of bionic T cells with costimulatory domain 4-1BBζ.
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In addition, bionic T cells armed with a HER2 or EGFR bispecific antibody showed high cytotoxic activity against cancer cells lines that were expressing HER2 or EGFR, and when these armed bionic T cells were used sequentially, the ability to kill target cells was even higher. For example, bionic T cells armed with a HER2 bispecific antibody killed about half of target cells (49.7%) when used alone, but when bionic T cells armed with a HER2 bispecific antibody were followed by bionic T cells armed with an EGFR bispecific antibody, 86.2% of target cells were killed.
Experiments also showed higher levels of both select cytokines in culture supernatants of tumor cells and bionic T cells armed with a HER2 or EGFR bispecific antibody compared with controls. In addition, after being exposed to the antigen, CD4+ and CD8+ T cells had increased expression of costimulatory molecules 4-1BB, ICOS, and OX40.
According to the study authors, the data indicate that “cytokines and chemokines show [an] immune-modulating and tumor-killing profile.”
Disclosure: Some of the abstract authors disclosed financial relationships with pharmaceutical companies or ownership of relevant patents related to the work. Carl June, MD, disclosed he is a cofounder of Tmunity Therapeutics, which is a company that develops adoptive cell therapies. For a full list of disclosures, please refer to the original study abstract.
Reference
Thakur A, Scholler J, Bliemeister E, June C, and Lum L. Superior antitumor activity of metabolically enhanced bispecific antibody armed CAR-less Bionic T cells. Poster presented at: the 34th Annual Meeting & Preconference Programs (SITC 2019); November 6–10, 2019; National Harbor, MD. Abstract P221.
