Page 51 - ITPS-8-3

INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

and is resistant to therapies targeting PD-1/PD-L1. The that promote the targeted expression of interleukin 6,
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use of multi-kinase inhibitor regorafenib with anti-PD-1 interferon gamma, and interleukin 2 toward guanylate
monoclonal antibody toripalimab has recently progressed cyclase-c (GCC19), a target expressed in 70% to 80% of
to early phases of clinical trials to treat metastatic CRC. CRC. A study analyzing the adverse effects of GCC19
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A Phase I/IIb trial analyzing the ORR and disease control CAR T-cell in patients with metastatic CRC revealed that
rate in CRC patients treated with this therapy reported a 93% of participants experienced a Grade 3 or higher adverse
15.2% response rate of the 42 patients who were treated event, primarily related to cytokine release syndrome
with the combination therapy; however, lower ORRs were (CRS). However, these adverse events were transient.
seen in patients with liver metastases (8.7%). This reduction The median PFS was significantly longer in patients who
in response in CRC patients with liver metastases is likely received higher doses (2 × 10 cells) of GCC19 CAR T-cell
6
due to resistance to checkpoint blockade, as the liver compared to those receiving a lower dose (1 × 10 cells),
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harbors a significant proportion of immunosuppressive with a PFS of 6 months versus 1.9 months, respectively.
cells that mediate this resistance. High levels of the Although the sample size was small, the results suggest
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anaerobic species Fusobacterium are also associated with potential clinical activity of GCC19 CAR T-cell therapy in
decreased response to the combination of regorafenib and patients with advanced-stage CRC.
toripalimab, and its presence can be used as a marker in Another antigen under investigation is
monitoring treatment resistance. In addition, the disease- carcinoembryonic antigen, commonly overexpressed in
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control rate was 36.4% in patients who were specifically CRC. A Phase I trial evaluating carcinoembryonic antigen-
treated with the recommended dose of 80 mg of regorafenib specific CAR T-cell therapy in 10 patients with metastatic
plus toripalimab. The study also noted that while 94.9% CRC revealed that seven achieved stable disease, with two
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of patients in the trial experienced an adverse event due 99
to the treatment, only 38.5% experienced a significant showing a reduction in liver metastases. Moreover, CRS
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Grade 3 or higher event. This response suggests that the was reported in only three patients, with one experiencing
a severe adverse event. While overall safety appeared
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combination treatment has a safety profile comparable to manageable, CRS remains the most common adverse event
that of the individual drugs, while providing the added and requires vigilant monitoring during trials to prevent
benefit of improved efficacy.
systemic complications.
Another clinical trial also investigated the efficacy and
safety of combination treatment with regorafenib and CAR T-cell therapy has also been used to target
toripalimab in 33 patients with microsatellite instability mesothelin (MSLN), a differentiation antigen normally
subsets of CRC, a malignancy typically considered non- expressed in the mesothelium but also highly expressed in
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immune-responsive due to resistance to ICIs, which is solid cancers, including in 48–61% of CRC cases. In a
often attributed to poor infiltration of immune cells into the pre-clinical study using MSLN-targeted CAR T-cells with
TME. A response to the treatment was seen in 16 patients, irinotecan in patient-derived xenograft mouse models,
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with 12 patients experiencing stability in their disease, significant antitumor activity was observed in MSLN-
with further analysis using a Kaplan–Meier survival curve positive cells – particularly with the CAR_R47 construct,
displaying a median PFS of 113 days and a Cox regression which targets the Region 1 epitope of MSLN – while no
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model demonstrating a 12.12% objective remission rate. effects were observed in MSLN-negative cells. Complete
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Safety assessment of the therapy showed an incidence rate tumor regression was noted in two of the five mice receiving
of Grade 3/4 adverse reactions of 9.09%, with the majority the combination treatment. Although these results are
of adverse events (33.3%) being hand-foot syndrome. encouraging, further validation should be considered in
Altogether, the current studies are exploring PFS, OS, and future clinical trials.
safety outcomes associated with different combination Despite early promise, CAR T-cell therapy in CRC
therapies, with the goal of optimizing the use of ICIs as faces multiple significant external factors that impact the
targeted cancer therapies in specific patient populations. potency and overall safety profile of CAR T-cell therapy,
including inherent immunosuppressive barriers; secretion
4.2. CAR T-cell therapy in colorectal cancer of immunosuppressive cytokines; heterogeneity of CRC

CAR T-cell therapy is showing promise in the treatment of tumors; and on-target, off-tumor effects that can lead to
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hematological malignancies but has scarce clinical data for severe toxicity and unintended damage in normal tissue.
solid tumors. However, there have been recent pre-clinical These limitations have hindered clinical translation.
studies investigating the effect of CAR T-cell therapy Future directions in overcoming these challenges
in the treatment of CRC. One investigational approach include optimizing T-cell persistence, identifying new
involving engineered T-cells incorporated modifications CRC-specific antigens, and designing combinatorial or

Volume 8 Issue 3 (2025) 45 doi: 10.36922/ITPS025140018