Immune Checkpoint Inhibitors in pMMR/MSS Colorectal Cancer

Hajj, Joanna El; Reddy, Sarah; Verma, Nilesh; Huang, Emina; Kazmi, Syed Mohammad Ali

doi:10.1007/s12029-023-00927-2

Cited by 7 publications

(6 citation statements)

References 107 publications

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“…The It has been reported that a small subset (~ 2%) of patients with pMMR/MSS colorectal cancer with a mutation in POLE and POLD1 enzymes and those without liver metastases have a higher chance of a response to ICI immunotherapy [50]. While the patient in the present case did not have POLE or POLD1 mutations, no liver metastases were present.…”

Section: Discussionmentioning

confidence: 46%

Objective Response after Immune Checkpoint Inhibitors in a Chemotherapy-Refractory pMMR/MSS Metastatic Rectal Cancer Patient Primed with Experimental AlloStim® Immunotherapy.

Hirschfeld,

Gurell,

Har-Noy

2024

Preprint

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Background: Immune Checkpoint Inhibitor (ICI) immunotherapy is most effective in immune effector cell infiltrated ‘hot’ tumor lesions, such as occurs in deficient mismatch repair, microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, most all metastatic CRC tumors are mismatch repair proficient/microsatellite stable (pMMR/MSS) ‘cold’ lesions, without significant immune cell infiltration, and are unresponsive to ICI. AlloStim®, is an experimental, allogeneic immunomodulatory cell therapy designed to convert ‘cold’ metastatic tumor lesions to ‘hot’ inflamed lesions. After AlloStim® immunotherapy, this cold to hot inflammatory mechanism can make it difficult to distinguish between pseudoprogression and actual progression on restaging CT scans, as inflamed metastatic lesions can appear larger and occult disease can appear as new small lesions. Methods: To explore whether radiological progression after AlloStim® immunotherapy is due to immune-flare or disease progression, we administered a short course of a combination ICI therapy to a pMMR/MSS chemotherapy-refractory metastatic colorectal cancer patient enrolled in the StimVax Phase IIb clinical study that presented with radiological progression after AlloStim® immunotherapy. Our rationale was that an accelerated response to ICI should occur if the lesions were inflamed, while if the enlarged lesions were due to disease progression there would not be a response. Results: Here we report a rapid, significant reduction in tumor burden in response to ICI administration in an AlloStim® primed pMMR/MSS mCRC patient with retroperitoneal and lung metastases. Conclusion: This rare objective response to ICIs in a pMMR/MSS mCRC patient supports further evaluation of the combination of AlloStim® with ICI immunotherapy in MSS mCRC and other cold or ICI refractory tumors. Trial registration: National Library of Medicine (NLM) at the National Institutes of Health (NIH). Registered 22 June 2020, https://clinicaltrials.gov/study/NCT04444622

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Section: Discussionmentioning

confidence: 46%

Objective Response after Immune Checkpoint Inhibitors in a Chemotherapy-Refractory pMMR/MSS Metastatic Rectal Cancer Patient Primed with Experimental AlloStim® Immunotherapy.

Hirschfeld,

Gurell,

Har-Noy

2024

Preprint

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“…Pembrolizumab was the first immune checkpoint inhibitor to receive FDA approval for the treatment of MSI-H or dMMR colorectal cancer, marking a significant advancement in precision medicine for this disease. 102,131 The integration of immune checkpoint inhibitors and immunotherapy into precision medicine for colorectal cancer involves the identification of patients who are most likely to benefit from these treatments. Molecular testing methods, such as assessing PD-L1 expression, MSI status, and dMMR, play a pivotal role in patient selection.…”

Section: Egfr Inhibitors and Ras Pathwaymentioning

confidence: 99%

“…Tumors with high CTLA-4 expression may indicate immune escape mechanisms and a more aggressive phenotype. Clinical trials are exploring the potential benefits of targeting CTLA-4 with immune checkpoint inhibitors to improve treatment outcomes in colorectal cancer patients. , …”

Section: Identification Of Actionable Biomarkersmentioning

confidence: 99%

“…This heightened mutational load provides an opportunity for immunotherapies, such as immune checkpoint inhibitors targeting PD-1, to be more effective in MSI-H and dMMR colorectal cancer. Pembrolizumab was the first immune checkpoint inhibitor to receive FDA approval for the treatment of MSI-H or dMMR colorectal cancer, marking a significant advancement in precision medicine for this disease. , …”

Section: Targeted Therapies In Precision Medicinementioning

confidence: 99%

“…Clinical trials are exploring the potential benefits of targeting CTLA-4 with immune checkpoint inhibitors to improve treatment outcomes in colorectal cancer patients. 131,132 The assessment of immune checkpoint markers as prognostic biomarkers also extends to tumor-infiltrating lymphocytes (TILs), which play a crucial role in antitumor immunity. The presence of a higher number of activated cytotoxic T cells among TILs in colorectal tumors is generally associated with a more favorable prognosis, suggesting that an effective immune response is mounted against the cancer.…”

Section: Tumor Microenvironment Factorsmentioning

confidence: 99%

See 2 more Smart Citations

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

Kiran,

Yashaswini,

Maheshwari

et al. 2024

ACS Pharmacol. Transl. Sci.

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Precision medicine is transforming colorectal cancer treatment through the integration of advanced technologies and biomarkers, enhancing personalized and effective disease management. Identification of key driver mutations and molecular profiling have deepened our comprehension of the genetic alterations in colorectal cancer, facilitating targeted therapy and immunotherapy selection. Biomarkers such as microsatellite instability (MSI) and DNA mismatch repair deficiency (dMMR) guide treatment decisions, opening avenues for immunotherapy. Emerging technologies such as liquid biopsies, artificial intelligence, and machine learning promise to revolutionize early detection, monitoring, and treatment selection in precision medicine. Despite these advancements, ethical and regulatory challenges, including equitable access and data privacy, emphasize the importance of responsible implementation. The dynamic nature of colorectal cancer, with its tumor heterogeneity and clonal evolution, underscores the necessity for adaptive and personalized treatment strategies. The future of precision medicine in colorectal cancer lies in its potential to enhance patient care, clinical outcomes, and our understanding of this intricate disease, marked by ongoing evolution in the field. The current reviews focus on providing in-depth knowledge on the various and diverse approaches utilized for precision medicine against colorectal cancer, at both molecular and biochemical levels.

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