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Published on: November 19, 2019
KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We Have All Been Waiting for
Ben Z Stanger1, Robert H Vonderheide1
1Abramson Cancer Center, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract:
Oncogenic RAS drives an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Inhibition of RAS signaling, as is now possible with an ever-increasing pharmaceutical portfolio, not only directly blocks tumor cells but also reverses immunosuppression, enabling infiltration of cytotoxic T cells and major alteration of the tumor microenvironment. In preclinical studies, the full antitumor effects of RAS inhibitors depend on T cells such that regressions in mice lacking T cells (or cross-presenting dendritic cells) are less deep and less durable than those in T cell-replete mice. Moreover, RAS inhibitors given with immune checkpoint blockade and immune agonists produce even more potent antitumor effects, especially in tumors with some amount of baseline T-cell infiltration. These findings set the stage for testing RAS inhibitors and immunotherapy in combination for PDAC, which is otherwise refractory to immunotherapy. Other immune partners might include vaccines, bispecific antibodies, and cell therapy. A major clinical opportunity eventually would be combining RAS inhibitors and immunotherapy in the adjuvant, neoadjuvant, and interception settings, provided this new class of drugs is developed keeping its immune-modulatory power in mind.
Insights
RAS inhibitors reverse immunosuppression in pancreatic cancer, enhancing T cell infiltration and anti-tumor effects. Combining RAS inhibitors with immunotherapy shows promise for treating this immunotherapy-refractory cancer.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Oncogenic RAS signaling promotes an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC).
- Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to current immunotherapies.
Purpose of the Study:
- To investigate the immunomodulatory effects of RAS inhibition in PDAC.
- To evaluate the potential of combining RAS inhibitors with immunotherapy for PDAC treatment.
Main Methods:
- Preclinical studies in mouse models of PDAC.
- Assessment of tumor microenvironment alterations and T cell infiltration upon RAS inhibition.
- Evaluation of combination therapies including RAS inhibitors, immune checkpoint blockade, and immune agonists.
Main Results:
- RAS inhibition reversed tumor-associated immunosuppression and promoted cytotoxic T cell infiltration.
- The anti-tumor efficacy of RAS inhibitors was dependent on T cells.
- Combination therapy with RAS inhibitors and immunotherapy demonstrated enhanced anti-tumor effects, particularly in tumors with existing T cell infiltration.
Conclusions:
- RAS inhibitors can reprogram the tumor microenvironment, making PDAC potentially responsive to immunotherapy.
- Combination strategies involving RAS inhibitors and various immunotherapies represent a promising clinical avenue for PDAC.
- Future clinical trials should consider RAS inhibitors and immunotherapy combinations in neoadjuvant, adjuvant, and interception settings.
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