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Peritumoral administration of immunomodulatory antibodies as a triple combination suppresses skin tumor growth without systemic toxicity. | LitMetric

AI Article Synopsis

  • Skin cancers, especially keratinocyte cancers, are the most frequent type of tumors, and while surgery is effective for early stages, they can recur and have the potential to spread. Recent studies on immunotherapies have shown promise in controlling skin cancers using checkpoint inhibitors, but these often come with unwanted side effects when used together.
  • This study explored a new approach by administering a combination of antibodies targeting PD-1, 4-1BB, and VISTA directly around the tumors, rather than through the bloodstream, to see if it could effectively treat skin tumors and stimulate immune responses without causing off-target toxicities.
  • Results indicated that local treatment effectively eliminated tumors with fewer side effects than intravenous methods, relied

Article Abstract

Background: Skin cancers, particularly keratinocyte cancers, are the most commonly diagnosed tumors. Although surgery is often effective in early-stage disease, skin tumors are not always easily accessible, can reoccur and have the ability to metastasize. More recently, immunotherapies, including intravenously administered checkpoint inhibitors, have been shown to control some skin cancers, but with off-target toxicities when used in combination. Our study investigated whether peritumoral administration of an antibody combination targeting PD-1, 4-1BB (CD137) and VISTA might control skin tumors and lead to circulating antitumor immunity without off-target toxicity.

Methods: The efficacy of combination immunotherapy administered peritumorally or intravenously was tested using transplantable tumor models injected into mouse ears (primary tumors) or subcutaneously in flank skin (secondary tumors). Changes to the tumor microenvironment were tracked using flow cytometry while tumor-specific, CD8 T cells were identified through enzyme-linked immunospot (ELISPOT) assays. Off-target toxicity of the combination immunotherapy was assessed via serum alanine aminotransferase ELISA and histological analysis of liver sections.

Results: The data showed that local administration of antibody therapy eliminated syngeneic murine tumors transplanted in the ear skin at a lower dose than required intravenously, and without measured hepatic toxicity. Tumor elimination was dependent on CD8 T cells and was associated with an increased percentage of CD8 T cells expressing granzyme B, KLRG1 and Eomes, and a decreased population of CD4 T cells including CD4FoxP3 cells in the treated tumor microenvironment. Importantly, untreated, distal tumors regressed following antibody treatment of a primary tumor, and immune memory prevented growth of subcutaneous flank tumors administered 50 days after regression of a primary tumor.

Conclusions: Together, these data suggest that peritumoral immunotherapy for skin tumors offers advantages over conventional intravenous delivery, allowing antibody dose sparing, improved safety and inducing long-term systemic memory. Future clinical trials of immunotherapy for primary skin cancer should focus on peritumoral delivery of combinations of immune checkpoint antibodies.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10831460PMC
http://dx.doi.org/10.1136/jitc-2023-007960DOI Listing

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