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Review
. 2023 Nov;320(1):100-119.
doi: 10.1111/imr.13273. Epub 2023 Sep 11.

"Hurdles race for CAR T-cell therapy in digestive tract cancer"

Marie-Noelle Kronig  1 , Marc Wehrli  1   2   3 , Diego Salas-Benito  2   3 , Marcela V Maus  2   3
Affiliations
Review

"Hurdles race for CAR T-cell therapy in digestive tract cancer"

Marie-Noelle Kronig et al. Immunol Rev. 2023 Nov.

Abstract

Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients with pancreatic cancer. Even though immunotherapy such as immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid cancer types, ICI are still restricted to a very small group of patients and seem to be more efficacious in combination with chemotherapy. Cellular immunotherapy such as CAR T-cell therapy has entered clinical routine in hematological malignancies with outstanding results. There is growing interest on translating this kind of immunotherapy and success into patients with solid malignancies, such as DTC. This review attempts to describe the major advances in preclinical and clinical research with CAR T cells in DTC, considering the most relevant hurdles in each subtype of DTC.

Keywords: CAR T cell; adoptive cell therapy; clinical trials; digestive tract cancer.

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Conflict of interest statement

Conflict of interest

M.V.M. is an inventor on patents related to CAR-T cell therapies held by the University of Pennsylvania (some licensed to Novartis) and Massachusetts General Hospital (some licensed to Promab and Satellite Bio). M.V.M. holds equity in 2Seventy Bio, TCR2, Century Therapeutics, Oncternal, and Neximmune, and has served as a consultant for multiple companies involved in cell therapies; MVM serves on the Board of Directors of 2Seventy Bio.

Figures

Figure 1.
Figure 1.. Structure and further CAR T cell generations.
A Molecular structure of scFv including linker composed of glycine or serine (G4S) and hinge region. B first generation CAR, C second generation CAR, D third generation CAR, E tandem CAR, F synNotch CAR, G fourth generation CAR (TRUCK), H cytokine secretion; scFv = single chain variable fragment, VH = variable region of heavy chain, VL= variable region of light chain, TM = transmembrane region, CD3z = CD3 zeta, P = phosphate, Costim = costimulatory domain 1 or 2; TF = Transcription factor. Created with BioRender.com.
Figure 2.
Figure 2.. CRC target antigens for CAR T cell therapy listed for clinical trials in 05/2023 on clinicaltrials.gov.
A) Percentage of clinical trials completed, recruiting, not yet recruiting and unknown status for the search terms “Colorectal” and “CAR”. A total of 39 trials is indicated. B) Percentage of target antigens in clinical trials recruiting patients with CRC for CAR treatment. Antigens are indicated as percentage from a total of 39 trials. Search terms included “Colorectal” and “CAR”. Date of search on www.clinicaltrials.gov May 2023.
Figure 3.
Figure 3.. PDAC target antigens for CAR T cell therapy listed for clinical trials in 05/2023 on clinicaltrials.gov
A) Percentage of clinical trials recruiting, active but not recruiting, not yet recruiting, completed and terminated for the search terms ‘pancreatic cancer’ (PDAC) and ‘CAR T’. A total of 51 trials are indicated, 3 trials have been withdrawn and have not been included. B) Percentage of target antigens in clinical trials recruiting patients with PDAC for CAR treatment. Antigens are indicated as percentage from a total of 51 trials. Search terms included “CAR T” and “Pancreatic cancer”; “Pancreatic Neoplasms”; “Pancreatic carcinoma”; “Pancreas cancer”; “Malignant tumor of pancreas”; “Cancer of the pancreas”; “Tumor of pancreas”. Date of search on www.clinicaltrials.gov May 2023.
Figure 4.
Figure 4.. Gastric target antigens for CAR T cells therapy listed for clinical trials in 05/2023 on clinicaltrials.gov
A) Percentage of clinical trials recruiting, active but not recruiting, not yet recruiting, completed and terminated for the search terms gastric cancer and CAR T. A total of 38 trials is indicated, 3 trials have been withdrawn and have not been included. B) Percentage of target antigens in clinical trials recruiting patients with gastric cancer for CAR T treatment. Antigens are indicated as percentage form a total of 35 trials. Search terms included CAR T and gastric cancer. Date of search on www.clinicaltrials.gov May 2023.
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