Abstract
Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. 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. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB’s in a broader patient population.
Highlights
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 cancers
Performed intraperitoneal (i.p.) injection of TALL-104, CD8+ human Cytotoxic T cells (CTLs), before treating with anti-PD-1 therapy i.p. twice weekly for 24 days to determine the effects of the therapy on tumor growth (Figure 1A)
The same therapy demonstrated a downward trend in tumor growth for HCT116 p53+/+ xenografts, though this difference was not www.oncotarget.com significant by the time mice were required to be sacrificed due to institutional policy and ethical concerns (Figure 1B, second graph blue line)
Summary
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 cancers. Efficacy of ICI’s is limited due to primary or secondary resistance. Among the non-responders to ICI’s, the phenomenon called hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth is observed in patients (5–29%) with a dramatic progression of disease [1, 2]. 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 [3,4,5]. 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
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