CAR-T Cells

CAR- T therapy heralds a new and innovative approach to cancer immunotherapy. The core concept is to reprogram a patient’s T cells externally with chimeric antigen receptors (CARs) that are then transfused back into the patient. The modified T cells can recognize the tumor cells expressing these antigens, and trigger a defense reaction. So far, only six CAR-T therapies have been FDA approved, all autologous (patient’s own T cells are modified) and primarily liquid cancers ( B cell malignancies). For solid tumors, the promise of the therapy is a hot and challenging area of research, and the first therapy has been approved for treating multiple myeloma.

Despite the progress, the state of the art processes in generating autologous CAR-T cells have several limitations.

  • Generating personalized T cells for every patient is prohibitively expensive ( $$ average cost)
  • Not all patients have adequate number of T cells at an advanced stage of cancer
  • Despite the CAR modifications, it is hard to predict the baseline state of exhaustion of their T cells and their ability to proliferate in vivo
  • Solid tumors present the additional challenge for the T cells to travel through a toxic and resistant microenvironment of the stroma, to cell the tumor.
  • Preventing the emergence of a “cytokine release syndrome” during the CAR-T treatment, an inevitable collateral damage that can lead to organ failure.
CRISPR technology, which is the most precise and targeted gene therapy method known till date, holds promise to address some of these problems. Most significant amongst these applications are in the development of allogeneic CAR-T cells, where modified T cells from healthy donors are available off-the-shelf . The strategy has promise of delivering this treatment with less turnaround time, lower cost and more potent T cells.

The major roles of CRISPR being investigated in CAR-T production are in

  • Preventing onset of graft vs host disease (GvHD): In allogeneic T cells, this phenomenon will cause a rejection of infused T cells. CRISPR directed editing can remove endogenous T cell receptor (TCR), MHC proteins and self-antigens.
  • Knocking out immune checkpoint inhibitors: PD-1, CTLA-4 and LAG3 that that in cancer cells are inhibited thereby reducing the release of interleukins, part of the defense strategy..
  • Moderating the Cytokine release syndrome: Knock out of certain toxic interleukins and simultaneous knock-in of certain desirable cytokines can boost cytokine production. Several of these strategies are in the preclinical models. Eg: Silencing of the TGF-beta signaling

Major challenges that are in optimization for CRISPR edited CAR-T are reduction of off-target effects in CRISPR editing and simultaneous knocking off/ in of multiple loci to reduce the GvHD, and cytokine release syndrome and release the inhibition on immune checkpoint inhibitors.

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