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Timer CAR-T (TCAR-T): A paradigm shift in CAR-T cell therapy

Conference Paper · October 2021

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10 authors, including:

Romy Roy Parampreet Kaur

Sree Chitra Tirunal Institute for Medical Sciences and Technology St. John's National Academy of Health Sciences
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Mufeeda Ck Shamsudheen Marakkar

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Cochin University of Science and Technology
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PrgmNr 2013 - Timer CAR-T (TCAR-T): A paradigm shift in CAR-T cell therapy

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Author Block: R. Roy1, P. KAUR2,1, C. Mufeeda1, S. Marakkar1, K. W. Johnson3, B. S. Glicksberg4, L.

Subramanian5, K. Yadav6, K. Shameer7, A. Cherian8; 1Molecular Robotics, Cochin, Kerala, India, 2M. S.
Ramaiah Univ. of Applied Sci., Bangalore, India, 3New York, NY, 4Icahn Sch. of Med. at Mount Sinai,
New York, NY, 5Courant Inst. of Mathematical Sci., New York Univ., New York, India, 6Engineering Med.,
Texas A&M Univ., Houston, TX, 7Mount Sinai Hlth.System, New York, NY, 8Max Planck Inst. for Heart
and Lungs Res., Bad Nauheim, Germany
Disclosure Block: R. Roy: None.
The development of effective targeted therapies with better survival and fewer side effects is crucial
for cancer treatment. Although CAR-T cell therapy has shown immense potential in cancer treatment,
off-target side effects, neurotoxicities, and cytokine release syndrome present unique challenges and
have hindered its widespread use. Since CAR-T cells are designed to be alive in the body for their
entire life span, it exacerbates the severe side effects. Thus, programming CAR-T cells to die after
their assigned function can help overcome some of these challenges. Here, we propose the
development of a new CAR-T approach to address these challenges. Briefly, we suggest that
developing genetically modified CAR-T cells that can be eliminated using external modulations
without compromising their therapeutic functions could address some of the shortcomings of the
current cell therapy systems. These timer CAR-T (TCAR-T) cells can significantly act temporally,
reduce long-term side effects, and be utilized during early tumorigenesis as they could be eliminated
upon successful tumor remission. The development of such cells is possible by overexpressing the
CAR protein and diphtheria toxin receptor together in the T-cells using a dual promoter virus vector.
Since the modified TCAR-T cells contain comparatively more diphtheria toxin receptors, they could be
highly sensitive and respond selectively to small doses of diphtheria toxin. The conditional removal of
CART-T cells could also significantly reduce cytokine release during CAR-T cell therapy. We envisage
that the validation TCAR-T approach could help ultra-personalize the cell and gene therapy offerings
in the near future.

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