2016 Archives | Alliance for Cancer Gene Therapy

Dendritic cells are potent antigen presenting cells capable of stimulating tumor immunity. Despite their promise as vectors for cancer vaccines, limited clinical efficacy has been observed to date. We have identified a fundamental metabolic pathway that is triggered within the melanoma microenvironment and that results in the potent suppression of dendritic cell function.

After identifying a fatty acid transporter as playing a critical role in this pathway, we have determined that the pharmacological inhibition of this transporter is capable of reversing this process of dendritic cell tolerization and significantly enhancing T cell activation. Based on these findings, we now propose to engineer a dendritic cell-based cancer vaccine that has been genetically silenced for this transporter and to test the impact of this modification both in a transgenic melanoma model as well as in advanced melanoma patients who are refractory to checkpoint inhibitor immunotherapy. In addition to generating more potent ex vivo DC-based vaccines, this work is aimed at validating this recently identified fatty acid transporter as a genetic target for future in vivo DC-targeted treatment strategies.

Recent clinical successes have revealed that the immune system can be successfully harnessed to fight cancer. Various strategies are utilized, including enhancing a patient’s ‘natural’ response to cancer as well as ‘redirecting’ a patient’s immune cells (‘T cells’) to the tumor using genetic engineering. While these T cell therapies have had major success in leukemias, they have not yet shown promise in the treatment of solid tumors.

T cells require an enormous amount of fuel to perform their tumor-killing functions. However, we have recently shown that in solid tumors, cancer cells evade immune responses in part by depriving the T cell of the ability to generate energy and depleting the local environment of nutrients.

In this Alliance for Cancer Gene Therapy funded research program, we will utilize genetic engineering to metabolically ‘reprogram’ tumor-specific T cells. Using this technology, they will become more fit to fight cancer for an extended period of time. We will test these T cells in animal models and translate these findings into human T cells as well. The goal is to generate super-soldier type T cells, those that can be both redirected to the tumor site, but also bolstered metabolically to support long-term and durable responses.

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.

Outcomes for osteosarcoma have not improved in more than two decades. The addition of “first generation” cytotoxic chemotherapy to surgery improved outcomes in the late 1980s, but additional gains have not been made since, despite increasing the doses of drugs given and the number of chemotherapy agents administered.

Clearly, advances in osteosarcoma require novel therapeutics capable of killing chemoresistant cancer cells. Evidence from many different disease settings demonstrates that immunotherapy can kill chemoresistant cancer. The challenge lies in developing a way to activate and harness the impressive power of human T cells to recognize osteosarcoma as foreign.

Gene therapy has provided new approaches to direct human T cells to recognize human cancers by engineering “chimeric antigen receptors” (CARs), which incorporate the binding portion of an antibody and the signaling portion of a T cell. CARs have worked well in acute leukemia and have activity in lymphoma, but have not yet mediated impressive effects on solid tumors.

My laboratory is working diligently to improve CARs for solid tumors. We have focused on engineering CAR T cells to recognize GD2, a fatty sugar (glycolipid) uniquely overexpressed on cancer cells, including osteosarcoma. We have already conducted a clinical trial of GD2-CAR in patients with osteosarcoma and neuroblastoma. In this study, we saw that the GD2-CAR T cells expanded after transfer, but did not persist beyond 1-2 months.

Successful immunotherapy in other solid cancers demonstrates that T cells must persist for several months if they are to have meaningful clinical effects. This project incorporates a series of improvement to the GD2-CAR therapy aimed at rendering GD2-CAR T cells more persistent, and thus more potent, in patients with osteosarcoma and neuroblastoma. Studies conducted in my laboratory demonstrate the modifying the GD2-CAR itself increases persistence and potency. In addition, modifying the way in which the T cells are grown, prior to transfer, enhances GD2-CAR persistence and potency. We also discovered that co-administration of a drug that depleted immune suppressive populations can render the GD2-CAR T cells more potent.

This protocol builds upon all of these advances, incorporating them into one trial, which will deliver a state-of-the-art, next generation gene therapy trial for the treatment of osteosarcoma and neuroblastoma. True clinical advances rarely result from one scientific breakthrough. Rather, effective cancer treatments most often result from iterative improvements that begin with careful observations from clinical trials, scientific innovation to overcome challenges, then retesting in clinical trials. The GD2-Persist Trial incorporates a series of iterative improvements that build upon careful clinical studies and innovative science, thus leveraging the power bedside-to-bench-to-bedside iteration to improve osteosarcoma therapy.      

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America and Wendy Walk.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. It is incurable, with average patient survival of about 13 months even with an aggressive therapeutic regimen consisting of maximal tumor resection, and concomitant chemotherapy and radiotherapy. One of the reasons for therapeutic failure is the complex functional heterogeneity in this brain tumor. In fact, not all cells are functionally identical in GBM, but a small population has properties reminiscent of normal stem cells, whereby they are uniquely responsible for tumor growth and recurrence. We call these specialized cells “cancer stem cells,” or tumor-initiating cells.

Whereas current treatments are relatively successful at targeting the other cells in this tumor, cancer stem cells have ways of evading current therapeutic intervention. We have recently shown that one feature that distinguishes cancer stem cells from the other cells in GBM is the way DNA is packaged. Cancer stem cells have regions of highly compacted DNA, which is caused by low levels of a protein that binds the DNA and relaxes its architecture.

We have designed a protein that can change DNA architecture and can be directed by us to any site in the human genome. We will use this engineered protein to unravel the DNA structure that is specifically found in the cancer stem cells of GBM patients.

We will provide proof-of-principle that altering DNA architecture is an effective way of targeting cancer stem cells. We will do so by testing the efficacy of our approach in a collection of patient-derived cancer stem cell cultures. We will then test the pre-clinical implication of our findings by transplanting GBM cancer stem cells in mice and treat their resultant “human” tumors with our engineered protein. We will then assess the effects of our treatment on tumor growth and recurrence. Essentially, our technology will enable us to perform a new kind of gene therapy by directly targeting DNA structure which is the ultimate determinant of cancer stem cell behavior.