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How Turning ‘Cold’ Tumors Into ‘Hot’ Ones May Improve Response to Immunotherapy

The proliferation of immunotherapeutics in the treatment of cancer over the past decade has revolutionized the way many cancers are treated, especially lung cancer and melanoma, as well as some blood cancers, including leukemia and lymphoma, drastically improving outcomes for many patients with these diseases, even in the metastatic setting. However, for most common cancers, such as pancreatic, colorectal, and breast cancers, immunotherapy in its different forms, including checkpoint blockers, vaccines, and chimeric antigen receptor (CAR) T-cell therapies, has not been as successful, and numerous studies are underway to discover why immunotherapies work or do not work in individual patients.

A recent laboratory study by Robert H. Vonderheide, MD, DPhil, Director of the Abramson Cancer Center of the University of Pennsylvania, and his colleagues, including Ben Z. Stanger, MD, PhD, Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, investigating the factors underlying pancreatic tumor immune heterogeneity and immunotherapy sensitivity, is shedding light on how to enhance immunotherapy based on the molecular structure of a patient’s tumor and activate the immune system to destroy cancer cells, thereby turning immunologically “cold” tumors into “hot” ones. Immunologically cold tumors, explained Dr. Vonderheide, are cancers that for various reasons contain few infiltrating T cells and are not recognized and do not provoke a strong response by the immune system, making them difficult to treat with current immunotherapies. Cancers that are classically immunologically cold include glioblastomas as well as ovarian, prostate, pancreatic, and most breast cancers.

[…] Have you launched clinical trials in patients using combinations of chemotherapy and checkpoint inhibitors?

Yes, we have a number of studies underway. The largest one is a randomized phase II study performed with the Parker Institute for Cancer Immunotherapy; it is investigating the combination of standard U.S. Food and Drug Administration–approved drugs for patients with metastatic pancreatic cancer and the anti–PD-1 monoclonal antibody nivolumab and an anti-CD40 monoclonal antibody called APX005M. In this clinical trial, one-third of patients receives chemotherapy plus nivolumab; one-third receives chemotherapy plus the anti-CD40 antibody; and one-third receives chemotherapy and both nivolumab and the anti-CD40 antibody.

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