Converting “Cold” Tumors Hot
Strategies to get cancer-killing immune cells to infiltrate and attack solid cancers
Cancer cells in solid tumors are tricky. They can evade the body’s natural immune defenses against abnormal cells. For therapies that leverage the immune system to be effective in treating solid cancers, the tumor-killing immune cells have to be active and they have to get into the tumor.
Unfortunately, many cancers are immune “cold,” meaning that there are no active cancer-killing immune cells within the tumor. Patients with these kinds of cancers will not respond to therapies like CAR-T cells, because the engineered cells won’t get into the tumor to kill it. Therapies based on blocking immune checkpoint inhibitors (Yervoy, Keytruda, Opdivo, Tecentriq, Bavencio, Imfinzi, Libtayo) also won’t be effective. Those treatments rely on infiltration of the tumor by functional cancer-killing cells of the patient’s immune system.
Researchers are testing multiple strategies to convert these immune cold tumors to hot ones. These include administering chemotherapy or radiation to trigger cell death in the tumor. These treatments cause tissue injury and trigger an immune response to the inflammation. Additionally, radiation or surgery, even biopsy, can physically disrupt the tumor, enabling the tumor-killing immune cells to penetrate. For many patients, such as breast cancer patients, surgery, chemotherapy, and radiation are among the first-line treatments. A challenge is determining the optimal timing of the delivery of immune-targeted therapy with such treatments. Many clinical trials are ongoing for breast cancer alone testing various combinations of immunotherapy with other treatments.
Another set of strategies involve using viruses or microbial-based cancer therapies to stimulate an immune response to the tumor. One approach has been to use oncolytic viruses, which are genetically engineered viruses that specifically infect and kill the tumor cells to trigger an immune response. Only T-VEC is approved by the FDA, but several others are in clinical trials.
Other studies suggest that the virus does not need to be alive to stimulate an anti-tumor immune response. Even injecting inactivated noninfectious virus that has not been engineered to kill cancer cells triggered anti-tumor immune responses in preclinical studies. One such study used the seasonal flu vaccine. The basis for this strategy that the vaccine has components of the pathogen, and these stimulate an immune response within tumor.
A counterintuitive investigational strategy is using drugs that inhibit the growth of blood vessels in the tumor. These drugs include Avastin, Inlyta, Cometriq, Nexavar, Afinitor, and Sutent. This strategy might work, because the immune cells do not properly transit across the immature vessels into the tumor. Thus, by “normalizing” the blood vessels so that they mature into stable vessels, the immune cells are able to cross the blood vessels and enter the tumor.
F. J. Esteva, V. M. Hubbard-Lucey, J. Tang, L. Pusztai, Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncology 2019, e175-e186. DOI: 10.1016/S1470–2045(19)30026–9
J. H. Newman, et al., Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer. Proc. Natl. Acad. Sci. U. S. A. 30 December 2019. DOI: 10.1073/pnas.1904022116