Research

1) Exploiting the naturally occurring canine model to improve gene-engineered cellular therapy:   Creating accurate models of cancer is hard. Most labs use mouse models of cancer — and we do this too for certain things. However, it is very important to be cognizant of what these models can tell us about human disease and where their limits are. Our lab studies cancer immunotherapy and many mouse models of human cancers have immunodeficiencies. Other mouse models have important differences with respect to the tumor biology. Because our lab is always coming up with new ideas for improving sarcoma immunotherapy with a focus on bringing treatments to the clinic, we need a great model for their development.

While sarcomas are (thankfully) relatively rare in humans, these cancers are one of the most common cancers in pet dogs. There is very good science showing that these canine tumors very closely resemble their human counterparts, probably in part because they develop in a natural way and may have a tumor evolution that also mirrors human disease. These are normal dogs with healthy immune systems. We have developed many processes and techniques for studying canine cancers and immunotherapies using gene engineered therapies and this work is currently moving at full speed. We have also developed relationships with academic veterinarians, key non-profit organizations (https://www.ccralliance.org) and currently have two active, enrolling trials in the veterinary clinic testing new gene engineered immunotherapies in dogs. While our main goal is to answer key questions regarding therapy for human sarcomas, we are also trying to help the pets on these trials as well as their families.

2) Improving Cell Therapy for Synovial Sarcoma and Myxoid/Round Cell Liposarcoma:  The early years of the Pollack Lab were entirely dedicated to tediously isolating, sorting, and expanding rare cancer specific T cells from the blood of cancer patients for analysis and therapy. As part of this work, we generated clinical grade protocols and ultimately cell-therapy sarcoma clinical trials with clinical responses that were unfortunately short-lived. We found that despite progression, these patients retained antigen expression and continued to have rare antigen presenting cells circulating in their peripheral blood. When we co-cultured isolated the rare cancer specific T cells from the patient’s blood with tumor lines in the lab, these cells would not kill tumor untreated however, after treatment with IL-15 they vigorously proliferated and efficiently killed targets. This is one of the phenomenon that we are very excited about exploring.

In correlative studies, we identified MHC down-regulation as an important means of immune evasion in these sarcoma. We established an investigator-sponsored trial supported, testing whether interferon gamma could up-regulate MHC in these tumors. That trial demonstrated the potential for interferon gamma to up-regulate MHC and recruit tumor specific T cells into the sarcoma immune microenvironment but also increased expression of PD-L1 in the tumor which led to a Cancer Immunotherapy Trials Network study of interferon gamma and anti-PD1 trial. This trial is complete and we are actively studying samples from this study; we believe this analysis will lead to fundamental indights that will alter future trials of both engineered T cells and vaccines in these terrible diseases.

3) Understanding the Changing T Cell Receptor Repertoire in the Sarcoma Immune Microenvironment:    The human body has an incredible diversity of T cells capable of recognizing all sorts of threats, including infections and cancers. Our early work analyzing the T cell repertoire in sarcomas demonstrated that certain sarcomas have a more robust and focused T cell response. More recently, we have focused on understanding the changing T cell repertoire for sarcoma patients on clinical trials. We have identified key T cell receptor sequences in certain clinical situations that we believe have important clinical significance. We have also been leaders in characterizing the sarcoma immune microenvironment both in its natural state and as it changes on immunotherapy trials. Our lab is actively working to isolate T cells with these sequences and to better understand their phenotype and function.