CAR T-cell immunotherapy in colorectal cancer

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In a recent study published in Frontiers in Immunology, researchers assessed the efficacy of chimeric antigen receptor (CAR) T-cells in the immunotherapy of colorectal cancer (CRC).

Background

CAR T-cells are a novel cell-based immunotherapy against cancer that is developed genetically. The application of CAR T-cells has transformed the treatment of hematological cancers. Before this therapy can be modified to treat solid tumors, such as colorectal cancer, extensive research is necessary. CAR T-cell treatment for colorectal cancer is in its infancy, and there is scarce clinical data available. Significant drawbacks of CAR T-cell treatment for colorectal cancer include significant toxicity, relapses, and an impenetrable tumor microenvironment.

Biological features of CAR T-cell engineering

In the present study, researchers assessed the CAR T-cell treatment for colorectal cancer with respect to existing knowledge, identified obstacles, and future perspectives.

CAR T-cell treatment is a personalized immunotherapy based on autologous or allogeneic synthetic CAR-expressing T-cells that have been genetically engineered. The CAR molecule consists of extracellular binding moieties, either a tumor-specific antigen (TSA)-sensing element or a single-chain fragment variable derived from an antibody. There is also a transmembrane anchor combined with signaling domains of the T-cell-receptor zeta chain complex and costimulatory molecules like CD28 and 4-1BB.

CAR T-cell activation arises from the direct and specific identification of tumor antigens by the extracellular domain, which leads to the killing of cancer cells. T-cells of a patient are typically transduced with gammaretroviral or lentiviral vectors to express CARs. After CAR T-cells are manufactured ex vivo, the patient undergoes lymphodepleting chemotherapy, if necessary, with subsequent CAR T-cell injection.

Principles of chimeric antigen receptor (CAR) T-cell therapy/CAR T-cell manufacturing process. CAR T-cell production includes normal T-cell extraction from the patient’s peripheral blood, followed by enrichment and CAR vector delivery, using viral or non-viral vector systems, into the T-cells in vitro. The CAR T-cells is subjected to expansion before being re-injected into the patient’s bloodstream. Patients usually receive a lymphodepletion before CAR T-cell administration to improve the expansion of adoptively transferred T-cells. The CAR T-cells proliferate and attack tumor cells that carry the specific antigen against which the CARs are directed

CAR T-cells play a promising role in the treatment of CRC

Surgical and chemotherapeutic first-line treatments for patients with CRC have long resulted in poor prognoses. The development of target-selective and effective medicines was made possible by a better comprehension of the processes contributing to tumor development and proliferation. Although CAR T-cells are excellent candidates against hematological malignancies, their efficacy against solid tumors, such as CRC, remains unverified. Several groups have concentrated on CAR T-cell biology preclinical research to establish safe treatment techniques and confirm their effectiveness in CRC.

Active and passive immunotherapy strategies in colorectal cancer. The immunotherapy treatments approved in recent years has widened the arsenal against colorectal cancer. Active immunotherapy includes cancer vaccines, checkpoint inhibitors, and oncolytic viruses. Cancer vaccine immunotherapy approaches are based on immunizing patients with cancer against their autologous cancers using either autologous tumor cell-derived vaccines, dendritic cell vaccines, peptide vaccines, DNA vaccines, or viral vector vaccines. Passive immunotherapy includes the use of immune checkpoint blockade, cytokines, and adoptive cell transfer of ex vivo educated immune cells

Epithelial cell adhesion molecule

One of the first preclinical investigations studied the lethal impacts of epithelial cell adhesion molecules (EpCAM)-directed CAR T-cells. Normal epithelial cells express EpCAM, a transmembrane glycoprotein, on their surface. Its overexpression is linked to enhanced cell proliferation, invasion, migration, and metastasis. Extensive peritoneal metastases and ascites formation were observed in an in vivo immunodeficient mouse model of late-stage metastatic cancer among humans. Repetitive injections of EpCAM-CAR T-cells inhibited the progression of peritoneal disease in xenografted mice with tumors.

Carcinoembryonic antigen

Carcinoembryonic antigen (CEA) is also a target of anti-CRC CAR T-cells that have been explored. CEA is an immunoglobulin glycoprotein overexpressed in various human malignancies, including colon, lung, gastric, pancreatic, and ovarian cancers. CEA is among the most significant prognostic and diagnostic tumor indicators and is overexpressed in over 98% of CRC tissue samples. Thus, CEA-targeted treatments have the potential to produce novel CRC therapy techniques. CAR T-cells targeting CEA have exhibited outstanding anticancer activity in vitro as well as in vivo, which was considerably enhanced by the addition of interleukins such as interleukin (IL)-12.

Epidermal growth factor receptor

In a xenograft model created by co-inoculation of tumor cells with CAR T cells, a study found that EGFRvIII-CAR T-cells combined with miR-153 completely eradicated the tumor. These findings suggested that miR-153 decreased indoleamine 2,3-dioxygenase (IDO)-1 expression among CRC cells and improved the efficacy of CAR T-cell treatment. Therefore, the combination of IDO1 inhibitors with CAR T-cells has the potential to function as an effective treatment for CRC and solid tumors.

Studies have also found that engineered cells that express a CAR that is capable of binding a fluorescein isothiocyanate (FITC) molecule (anti-FITC CAR T-cells) improved the ability of CAR T-cells to treat mice with estimated glomerular filtration rate (eGFR)-positive CRC tumors. In an immunocompromised mouse model, unique interactions between anti-FITC CAR T-cells and FITC-labeled cetuximab slowed the progression of colon cancer.

CAR T-cell studies for CRC

Ongoing studies investigate the application of CEA-specific CAR T-cells in patients with CEA-positive CRC. The goal is to verify efficacy and safety, as well as to determine the right doses and infusion schedule. Another objective of these investigations is to identify adverse effects, particularly cytokine release syndrome. Protocols for administration include hepatic and systemic transarterial delivery, vascular intervention, and intraperitoneal infusion, while the outcomes are awaited.

Also under evaluation is a novel combinatorial technique involving human epidermal growth factor receptor 2 (HER2)-specific CAR T-cells along with an oncolytic adenovirus (CAdVEC). Oncolytic adenoviruses reproduce and propagate exclusively within tumors, augmenting their cytotoxicity, enhancing tumor penetration, and reverting immune suppression. CAdVEC is a modified adenovirus with immunostimulatory components. Currently, Phase 1 trials are evaluating the efficacy and safety of HER2 CAR T-cells combined with oncolysis.

Conclusion

Overall, the study findings showed that CAR T-cells continue to garner evidence supporting their application as a viable immunological method of cancer treatment. This strategy has significantly improved patient treatment in hematological malignancies.

Journal reference:

Ghazi, B. et al. (2022) "CAR T-cells for colorectal cancer immunotherapy: Ready to go?", Frontiers in Immunology, 13. doi: 10.3389/fimmu.2022.978195. https://www.frontiersin.org/articles/10.3389/fimmu.2022.978195/full