Bedside to Bench: Investigating Response & Resistance Mechanisms to Immune Checkpoint Therapy
Dr. Padmanee Sharma, professor of genitourinary medical oncology and immunology at MD Anderson Cancer Center, presented an overview of immune checkpoint inhibitors (ICI) and how she has spent her research career studying the response and resistance mechanisms to these agents.
As background, it was highlighted that while the idea of cancer immunotherapy has been around for over a century, there was not regarded to be persuasive evidence that it could become an impactful anti-neoplastic therapeutic method for many cancers. In the 1990’s, FDA approvals of BCG vaccine and IL-2 for the treatment of GU and other cancer types were some of the initial advances made in modern cancer immunotherapy. These were subsequently followed by the approval of monoclonal antibodies, such as rituximab and trastuzumab.
As of today, the most impactful development within the field of cancer immunotherapy occurred through the characterization of T cell inhibitory pathways, including the ability to blockCTLA-4 to CD80/86 and PD-1 to PD-L1 interactions. Anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies are now a vital component of many cancer treatment regimens due to their ability to “wake up” inactive T cells and promote T cell-based killing of tumor cells. These successes have occurred not only in cases of metastatic cancer but also the neoadjuvant/adjuvant setting, such as in Dr. Sharma’s trial using neoadjuvant ipilimumab (anti-CTLA-4 antibody) for localized bladder cancer treatment. In this study, she and colleagues found that intratumoral B and T cell populations significantly increased following ipilimumab treatment and that ICOS-high CD4+ T cells were found both in peripheral blood and tumor tissue. Thus, ICOS/ICOSL is another emerging pathway that immunotherapeutics could be designed to target.
Challenges of immunotherapy resistance were also highlighted, with particular focus on prostate cancer. For example, prostate cancers are generally considered to have immunologically “cold” microenvironments and only a small subset of prostate cancers have been found to be responsive to ICIs. A study of ipilimumab-treated patients with prostate cancer showed that anti-CTLA-4 antibody therapy causes a compensatory increase in T cells expressing PD-L1 and another checkpoint molecule, VISTA. Upon studying the microenvironment of prostate cancer metastases, it has also been found that soft tissue metastases show increased Th1 cells and decreased Th17 cell populations after ICI treatment, promoting effector T cell activity. Interestingly, metastatic prostate cancer bone lesions tend to show the opposite in that they had low Th1 cell levels and high Th17 cell levels following ICI therapy (Jiao S et al, Cell 2019). Moreover, these bone tumors promoted osteoclast-mediated bone resorption as well as secretion of IL-6 and TGF-beta, cytokines linked to poorer survival rates in several types of cancer. TGF-beta prevents Th1 lineage development, however, blockade of TGF-beta allows for the recovery of Th1 subsets and expansion of CD8+ T cells. Moreover, in murine models with ICI-resistant bone metastases, the addition of a TGF-beta inhibitor to ICI treatment regressed bone disease compared to ICI alone.
Going forward, there is much to still learn about the resistance mechanisms by which ICI effects may be blunted and how to identify other novel targets to assist in promoting more “hot” immunologic tumor environments which will be amenable to cancer immunotherapeutics.