Activatable Cytokines as Novel Agents to Promote Immune Responses to Prostate Cancer
Abstract
There is increasing evidence that the immune response to many cancers, including prostate cancer, can be clinically significant. Exciting recent clinical studies in cancer patients have shown that immune responses to many tumors are more common than previously realized. If harnessed correctly, these can result in clinical responses and even potential cures. Importantly, the immune system has the capacity to reach tumors even if they have spread. While very promising, these immune-based approaches have still only worked in a fraction of patients. One roadblock is that many tumors have developed means to limit or even turn off immune responses that otherwise may kill the tumor cells. We are developing a new means of boosting immune responses by changing the microenvironment of growing tumors to one that actively enhances immune responses. Our approach is to actively change the mix of critical molecules called cytokines at the tumor site. Cytokines are potent mediators of immune responses. Most cytokines are produced and act locally. Cytokines have been used previously in cancer treatment with some successes, but side effects limit both their use and efficacy. To reach cancer cells that may spread, cytokines have often been given so they can circulate throughout the body. However, their potent effects, as well as their ability to affect many different cells, are one reason that cytokines have many serious side effects when given in this way. These unwanted side effects can include the massive release of additional cytokines by stimulated cells that has been termed a "cytokine storm." This cytokine storm can be very serious and greatly limits the use of cytokines. Our overall goal is to develop a means to overcome this problem while maintaining the benefits of the cytokine treatment. In this proposal, we are developing a new form of cytokine that is initially inactive but which becomes functional at the site of growing tumors due to the high local expression of proteases by prostate tumors. Here we will test the safety and efficacy of this approach using FPs that contain Interleukin-2 or Interleukin-12, two potent cytokines that can stimulate anti-tumor immune cells, in two relevant mouse models of prostate cancer. The short-term impact is to firmly establish "proof of concept" of this novel approach. Importantly however, an analogous approach could be developed using human cytokines. In this light, it is notable that one of the cytokines we are testing is a form of IL-2 that can be activated by proteases. The Food and Drug Administration has already approved an unmodified form of IL-2 for the treatment of some human cancers. This may make the translation to patients easier. In the long term, protease activated cytokines could be used in patients where they might dramatically impact the immune responses to tumors. We believe this approach can be used to boost the body s own immune response to tumors. Because cellular immune effectors can travel throughout the body, these cells have the capacity to kill tumor cells wherever they might be. However, we believe the approach we are developing can be also used in combination with other immunotherapy approaches to make it even more effective. We thus believe this can ultimately be translated to patient care and leading to improved treatment of prostate cancer and even potentially result in cures for cancers that have spread.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710214
Entities
People
- John Frelinger
Organizations
- United States Army
- University of Rochester