2026-03-17
CAR-T cells in colorectal cancer: the challenge of solid tumors
Oncology
By Ana Espino | Published on March 17, 2026 | 3 min read
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Despite advances in surgery, chemotherapy, and targeted therapies, metastatic CRC continues to carry a poor prognosis. Therapeutic options remain limited after failure of standard treatment lines.
Immunotherapy has transformed the management of certain hematologic malignancies, particularly through CAR-T cells. However, their efficacy in solid tumors, including CRC, remains limited by several major barriers: an immunosuppressive tumor microenvironment, antigen heterogeneity, stromal barriers, and the risk of “on-target, off-tumor” toxicity.
This review, published in the Journal of Clinical Oncology (2025), analyzes emerging antigen targets, recent clinical trial results, and innovative strategies aimed at optimizing CAR-T efficacy in CRC.
The authors first outline the CAR-T manufacturing process: leukapheresis, activation, genetic modification, expansion, lymphodepletion, and reinfusion. Second- and third-generation CARs incorporate costimulatory domains such as CD28 or 4-1BB, improving persistence and cytotoxic activity.
Several tumor antigens have been evaluated.
CEA has been tested in a phase I trial involving 10 patients with metastatic CRC. Seven patients achieved disease stabilization, including two durable responses beyond 30 weeks. Cytokine release syndrome (CRS) occurred in three patients, including one severe case.
GUCY2C appears particularly promising. In a phase I trial, the IM96 therapy demonstrated an objective response rate (ORR) of 26.3% and a disease control rate (DCR) of 73.7%, with a median progression-free survival of 7 months at higher doses. The GCC19CART product achieved an ORR of 40% in certain cohorts, with a reported median overall survival of 22.8 months.
Other targets include LGR5, a cancer stem cell marker, as well as CDH17, EpCAM, and MSLN. Some approaches have shown robust antitumor activity in preclinical models. However, severe pulmonary toxicities have been reported with mesothelin-targeted CAR-T cells, highlighting the challenge of antigen specificity.
The authors then detail biological barriers. The CRC tumor microenvironment is enriched with regulatory T cells, tumor-associated macrophages, and immunosuppressive cytokines such as TGF-β. Antigen heterogeneity promotes tumor escape, while the dense extracellular matrix limits cellular infiltration.
To overcome these limitations, several strategies are emerging: “armored” CAR-T cells secreting IL-12, TRUCK cells that modulate the microenvironment, bispecific or logic-gated CAR-T designs to reduce off-target toxicity, and combinations with checkpoint inhibitors such as pembrolizumab.
Patient selection may also improve outcomes. Molecular subtypes such as CMS1 (MSI-immune) appear more favorable due to a more immunologically active microenvironment.
Metastatic colorectal cancer remains a poor-prognosis disease despite current treatments. Major challenges include tumor-induced immunosuppression, antigen heterogeneity, and potential toxicity.
The aim of this review was to assess the potential of CAR-T cells in CRC by analyzing targets, clinical outcomes, and technological innovations. The data show encouraging signals of efficacy, particularly with GUCY2C, LGR5, and CDH17, along with generally acceptable safety profiles in early-phase trials.
However, the results are derived from early-phase, often non-randomized studies with small sample sizes. Target-specific toxicities, particularly pulmonary events with certain antigens, require careful antigen selection.
Future directions rely on optimizing costimulatory domains, developing allogeneic “off-the-shelf” approaches, combination strategies, and refined molecular patient selection. Ultimately, advanced CAR-T engineering could transform CRC management and pave the way for truly personalized cellular immunotherapy in solid tumors.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Despite advances in surgery, chemotherapy, and targeted therapies, metastatic CRC continues to carry a poor prognosis. Therapeutic options remain limited after failure of standard treatment lines.
Immunotherapy has transformed the management of certain hematologic malignancies, particularly through CAR-T cells. However, their efficacy in solid tumors, including CRC, remains limited by several major barriers: an immunosuppressive tumor microenvironment, antigen heterogeneity, stromal barriers, and the risk of “on-target, off-tumor” toxicity.
This review, published in the Journal of Clinical Oncology (2025), analyzes emerging antigen targets, recent clinical trial results, and innovative strategies aimed at optimizing CAR-T efficacy in CRC.
Which targets truly deliver?
The authors first outline the CAR-T manufacturing process: leukapheresis, activation, genetic modification, expansion, lymphodepletion, and reinfusion. Second- and third-generation CARs incorporate costimulatory domains such as CD28 or 4-1BB, improving persistence and cytotoxic activity.
Several tumor antigens have been evaluated.
CEA has been tested in a phase I trial involving 10 patients with metastatic CRC. Seven patients achieved disease stabilization, including two durable responses beyond 30 weeks. Cytokine release syndrome (CRS) occurred in three patients, including one severe case.
GUCY2C appears particularly promising. In a phase I trial, the IM96 therapy demonstrated an objective response rate (ORR) of 26.3% and a disease control rate (DCR) of 73.7%, with a median progression-free survival of 7 months at higher doses. The GCC19CART product achieved an ORR of 40% in certain cohorts, with a reported median overall survival of 22.8 months.
Other targets include LGR5, a cancer stem cell marker, as well as CDH17, EpCAM, and MSLN. Some approaches have shown robust antitumor activity in preclinical models. However, severe pulmonary toxicities have been reported with mesothelin-targeted CAR-T cells, highlighting the challenge of antigen specificity.
The authors then detail biological barriers. The CRC tumor microenvironment is enriched with regulatory T cells, tumor-associated macrophages, and immunosuppressive cytokines such as TGF-β. Antigen heterogeneity promotes tumor escape, while the dense extracellular matrix limits cellular infiltration.
To overcome these limitations, several strategies are emerging: “armored” CAR-T cells secreting IL-12, TRUCK cells that modulate the microenvironment, bispecific or logic-gated CAR-T designs to reduce off-target toxicity, and combinations with checkpoint inhibitors such as pembrolizumab.
Patient selection may also improve outcomes. Molecular subtypes such as CMS1 (MSI-immune) appear more favorable due to a more immunologically active microenvironment.
Personalization as the key to performance
Metastatic colorectal cancer remains a poor-prognosis disease despite current treatments. Major challenges include tumor-induced immunosuppression, antigen heterogeneity, and potential toxicity.
The aim of this review was to assess the potential of CAR-T cells in CRC by analyzing targets, clinical outcomes, and technological innovations. The data show encouraging signals of efficacy, particularly with GUCY2C, LGR5, and CDH17, along with generally acceptable safety profiles in early-phase trials.
However, the results are derived from early-phase, often non-randomized studies with small sample sizes. Target-specific toxicities, particularly pulmonary events with certain antigens, require careful antigen selection.
Future directions rely on optimizing costimulatory domains, developing allogeneic “off-the-shelf” approaches, combination strategies, and refined molecular patient selection. Ultimately, advanced CAR-T engineering could transform CRC management and pave the way for truly personalized cellular immunotherapy in solid tumors.
Read next: Medicinal plants: an asset against colorectal cancer?
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
Last press reviews
Colorectal cancer: detecting disease before the tumor appears?
By Ana Espino | Published on March 17, 2026 | 3 min read<br><br><br>...
CAR-T cells in colorectal cancer: the challenge of solid tumors
By Ana Espino | Published on March 17, 2026 | 3 min read<br><br><br>...
Reprogramming the immune system: a new strategy against ovarian cancer
By Elodie Vaz | Published on March 16, 2026 | 3 min read ...