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Oncotarget: Hyperprogression of a mismatch repair-deficient colon cancer


FOR IMMEDIATE RELEASE
2021-11-01

Oncotarget published "Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab" which reported that immunotherapy is an established treatment modality in oncology.

However, in addition to primary or acquired therapy resistance with immune checkpoint blockade, hyperprogressive disease or hyperprogression with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient human colon carcinoma HCT116 p53-null tumor xenograft, these authors observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration.

Human cytokine profiling revealed changes in IFN-, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d.

Dr. Wafik S. El-Deiry said, "Immune checkpoint inhibitors (ICI's) have revolutionized cancer treatment with significant responses, and an explosion of new single or combination therapies involving the immune system have been approved by the FDA for multiple cancer."

Figure 6: Cytokine profiling of in vitro CRC cell lines and TALL-104 co-cultures. CRC cell lines and TALL-104 co-cultures. Cytokine analysis was conducted on co-culture media following 24 hours of co-culture between CRC cell line and TALL-104, with and without 25 μg/mL pembrolizumab treatment. All experiments were conducted in quadruplets. (A) Heat map of cytokine expression levels in culture media following 24 h co-culture. (B) Significant cytokine differences in treatment response upon administration of anti-PD-1 therapy between cell lines.

Efficacy of ICI's is limited due to primary or secondary resistance. Genomic alterations such as MDM2 or MDM4/MDMX amplification, EGFR alterations and several genes located on chromosome 11q13 have been reported to be linked to HPD.

Currently, one of the major obstacles in understanding the pathophysiology of HPD/HP is a lack of preclinical experimental in vivo models, making it difficult to study this phenomenon.

One of the major obstacles in understanding the pathophysiology of HPD/HP is a lack of preclinical experimental in vivo models, making it difficult to study this phenomenon

The El-Deiry Research Team concluded in their Oncotarget Research Output, "we report a novel humanized MMR-d colon cancer HPD model which may serve as a tool to facilitate understanding of the pathophysiology of HPD and which may help identify biomarker(s) and novel therapeutic targets or strategies for cancer immunotherapy. Given its relatively low cost, feasibility and relatively simple establishment procedures, the current working humanized HPD/HP mouse model may be useful in studying human CTL's and immune checkpoint inhibitors in other cancer cell line–derived human xenografts, patient-derived xenografts or patient-derived organoid systems. Future experiments can test patient-derived autologous T-cells, other immune cells or subsets, as well as potential impact of hormones and gender of mice as biological variables. A variety of gain-of-function or loss-of-function screens could be performed to characterize the molecular determinants of HPD/HP in vivo and this may uncover additional biomarkers or synergies to anticipate and prevent or treat HPD/HP in patients receiving immune checkpoint blockade therapy."

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DOI - https://doi.org/10.18632/oncotarget.28086

Full text - https://www.oncotarget.com/article/28086/text/

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

Keywords - cancer immunotherapy, immune checkpoint inhibitors, hyperprogressive disease (HPD), hyperprogression (HP), humanized mouse

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