What are the next-generation T cell immunotherapies?

It’s no secret that T cell immunotherapies (CAR, TCR, and BiTE) are really red hot. Companies like Novartis, Juno Therapeutics, Amgen/Kite Pharma, Adaptimmune/Eli Lilly, Immunocore/AstraZeneca/Genentech/GlaxoSmithKline, Cellectis/Pfizer/Servier, Bluebird Bio/ Celgene, Johnson & Johnson/Transposagen Biopharmaceuticals, and China-based CARsgen are racing to commercialize this technology.

With the field increasingly crowded, many companies and investors are eyeing the next-generation T cell immunotherapies. Here is a good read from Atlas Venture[1] that missed the opportunity to invest CAR-T cell immunotherapy at early stage:

Atlas was very close to jumping into that race in the months that followed the Penn-Novartis announcement, but we failed to seize the opportunity fast enough for a variety of reasons. About a year ago, sensing the CD19 race wasn’t one where we could compete to win as early stage venture investors, we began to shift our focus to “next generation” approaches in the CAR-T space. These include things like suicide switches to turn them off, alternative solid tumor antigen approaches, and allogenic off-the-shelf concepts.

I’m glad that Atlas has summarized the next generation approaches in the space of T cell immunotherapy. The field has been marred by concerns over safety issues (cytokine storm), cost of manufacture ($500,000/patient), the difficulties to find solid tumor antigens that are expressed only on cancer cells, and how regulators will view the unusual and complicated treatment[2].

One of the problems with current CAR-T cells is that the cells expand in vivo and cannot be turned-off, resluting in unpredictable and uncontrollable immune responses and raising even great safety concerns. Bellicum Pharmaceuticals (NASDAQ: BLCM) designed a “switch” to control the the activation and proliferation of the CAR-T cells.

Unum Therapeutics equipped T cells with a “socket”, known as CD16, to load the Fc portion of monoclonal antibodies[3]. This technology, known as ACTR, enables T cells to attack tumor cells in an antibody-directed manner. ACTR-T cells are not restricted to a single antigen but instead can be universally applied to augment any antibody-directed therapy with a cell-surface antigen. Moreover, the ACTR-T cells treatment can be turn off by discontinuing the the use of the antibodies.

Frence-based Cellectis knocked out TRAC and CD52 gene via TALEN gene editing technology to generate TCR/CD52-deficient CAR-T cells, overcoming the key barriers of allogeneic T cells transplantation. These off-the-shelf CAR-T cells have the potential to be standardized with consistent quality and to significantly cut the cost of manufacture. Johnson & Johnson, partnering with Transposagen Biopharmaceuticals, is doing something similar. Novartis and Atlas Venture launched a startup called Intellia Therapeutics to explore the uses of CRISPR/CAS9 gene editing technology on CAR-T cells and hematopoetic stem cells.

[1] Bruce Booth. Cellular Immunotherapy & Unum Therapeutics: Out Of Many, One.

[2] Nature. 2014, 516(7530), 156.

[3] Cancer Res. 2014, 74(1), 93-103.

Related Articles:

CAR-T cell immunotherapy: could Cellectis be a game changer?

CRISPR/CAS9 patent fight spreads gobally, are you ready?

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