Malignant brain tumors carry a dismal prognosis despite surgery, chemotherapy, and radiation, hence new therapeutic approaches are needed. New strategies are being investigated using modified viruses (termed “vectors”) to infect cancer cells and deliver genes that serve as blueprints to make therapeutic proteins inside the cancer cells themselves.  

Until recently, most researchers used viral vectors that could deliver therapeutic genes to the initially infected tumor cells but are rendered incapable of infecting any additional cells. However, such ‘non-replicating’ vectors were found to have limited benefit, because not enough tumor cells could be reached.  

A newer approach is to use virus vectors that actively replicate themselves and can spread forth from the initially infected cancer cells within tumors, but not in normal tissues, thereby continuing to infect more cancer cells even as the cells continue to proliferate. These tumor-selectively spreading viruses are used to deliver a “suicide gene,” which converts a non-toxic ‘trigger’ compound (“prodrug”) into a DNA synthesis-blocking chemotherapy drug. Because this virus causes the chemotherapy drug to be generated selectively and directly within the infected tumor itself, there are few adverse side effects.  

The first version of this type of therapeutic virus has shown highly promising results in early-stage clinical trials and is currently being tested in an international Phase 2B/3 trial for recurrent brain cancer. 

We recently discovered that this approach can also activate the immune system to attack tumors. Hence, in this Alliance for Cancer Gene Therapy funded study, we examine whether brain tumors that show a high rate of new mutations, which can be recognized by the immune system, may be correlated with better responses to this treatment.  

We also propose to develop a new tumor-selectively spreading virus vector that delivers a different “suicide gene” which cross-links DNA and thereby generates new mutations for the immune system to attack, and we further propose to combine this mutagenic DNA cross-linking suicide gene therapy with strategies to overcome immune blockade (“checkpoint”) mechanisms within tumors.  

Finally, we will conduct preclinical studies to evaluate the safety of this new virus vector for use in a future clinical trial. If the proposed preclinical studies are successful in validating the safety, efficacy, and mechanism of action for this new immunogenic suicide gene therapy, combined with immune checkpoint inhibition, we anticipate that this approach can be rapidly translated to the clinic in collaboration with a biotech partner that is already testing our previously developed virus vector in clinical trials.  

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

Ovarian cancer is the most lethal gynecologic cancer. However, women with evidence of immune cells in their ovarian cancer, specifically T cells, have an improved overall survival. This suggests that T cells control ovarian cancer growth.  

Patient T cells can now be grown to large numbers outside of the body and then reinfused back into the same patient in a process referred to as adoptive T cell therapy. To allow these T cells to “see” the cancer cells, they are engineered outside of the body to express a tumor-sensor called a CAR. Patient T cells genetically engineered to express a CAR can recognize a cancer antigen, such as CD19. Transfer of these anti-CD19 CAR T cells back to terminally diseased patients results in cancer remission in ~90% of treated patients with certain forms of leukemia.  

In order to bring this form of therapy to women with ovarian cancer, we propose to engineer patient T cells to recognize an antigen called folate receptor-alpha, which is expressed by up to 90% of ovarian cancers, and use them to treat women with recurrent ovarian cancer, a disease which kills more than 14,000 women each year, and for which there are no effective treatment options. These CAR T cells can effectively and comprehensibly kill human ovarian cancer cells in mice. The opportunity now exists to provide this form of cancer gene therapy for our patients. Here, we propose conducting a clinical trial to test whether these CAR T cells are safe and effective in women with recurrent ovarian cancer.

Patients with metastatic synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCL) urgently need better treatment options. Therapies that employ anti-cancer immune T cells are proving effective against certain other malignancies, and SS and MRCL are ideal targets for this very promising approach. Both sarcoma types consistently express the NY-ESO-1 protein (AKA: antigen).  

Our group and others have shown that NY-ESO-1-specific T cells can attack SS and MRCL tumors in patients, but we need to further improve this therapy to produce more consistent, complete and durable responses. Most T cell therapies use CD8+ T cells, but CD4+ T cells might also be critical for effective treatment of these diseases. CD4+ T cells directly support CD8+ T cells and activate the ‘antigen-presenting’ cells (APC) that help CD8+ cells recognize tumor antigens.  

We can genetically engineer T cells to recognize NY-ESO-1 by engineering them to express a T cell receptor (TCR). We isolated the genes for two highly active TCRs specific for NY-ESO-1, one to be used in CD4+ cells and one to be used in CD8+ T cells. These TCRs were discovered in a very unique way, by using mice that had been engineered to have human immune system components. We are now ready, for the first time, to combine both genetically engineered CD4+ and CD8+ T cells.  

We will also precisely irradiate tumors to damage them and help our infused T cells recognize the tumor. We propose a first-in-human, first-in-class clinical trial for SS and MRCL patients addressing a fundamental question in cancer immunotherapy, i.e., are both CD8+ and CD4+ T-cell functions necessary for optimal response? This trial will evaluate the safety and efficacy of the engineered T cells and using biopsy samples, we will analyze the changes that occur in the tumor following the treatment.  

If successful, the proposed studies could transform the treatment paradigm for patients with SS and MRCL and address fundamental questions in immunology, potentially advancing novel strategies that can broadly improve immunotherapy efficacy and patient outcomes.

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