Massachusetts Archives - Page 7 of 14

Roberto Chiarle, M.D.

Funded by Bristol-Myers Squibb

Neuroblastoma is the second most common tumor in childhood accounting for 7% of all children with cancer. There are about 800 new cases of neuroblastoma each year in the US. Treatments for neuroblastoma include surgery when tumors are localized or chemotherapy and radiation therapy when tumor spreads to other parts of the body. Cure rates are high for low-risk children, but only about 50% for high-risk children such as those whose tumor has spread. For these reasons, neuroblastoma is still the deadliest cancer in the childhood. With our research we aim at increasing the cure rates of neuroblastoma, particularly in high-risk children. To achieve this goal, we will harness the immune system of the children by instructing their lymphocytes to specifically identify a molecule called ALK in tumor cells. To obtain the highest potency and accuracy, we will exploit not only one immunotherapy, but rather a novel dual immunotherapy that will combine a cancer vaccine with engineered lymphocytes, both primed to recognize the same ALK target on tumor cells. This novel concept of dual immunotherapy will be tested in mouse models of neuroblastoma and will provide essential information on how the immune system can be exploited to target this tumor. These findings will lay the foundation for future clinical trials that will exploit this dual immunotherapy approach in children.

Steven Barthel, Ph.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

It is now clear that our immune system has the capacity to both recognize and destroy cancer cells. Unfortunately, tumor cells escape this immune-mediated destruction by activating inhibitory switches to turn off T-cells. These switches, called immune checkpoint receptors (ICR), are now being targeted in early-phase clinical cancer trials in hopes of restoring and boosting immune-targeted killing of cancer.

However, despite showing promise in animal models of cancer, it remains unclear whether drugs targeting more recently identified ICRs will work in humans. Most importantly and a major focus of this proposal, while ICR therapies were previously assumed to bind and target only immune cells as noted above, our data newly identifies ICR expression directly on cancer cells along with therapeutically promising anti-cancer as well as pro-tumorigenic activities. What’s more, levels of cancer cell-ICRs could be dynamically regulated by cytokine stimulation. Overall, these findings raise unanswered questions on ICR-specific drug safety, specificity, potency and optimization that challenge existing, even false, assumptions within the immunotherapy field and invite further inquiry of these entirely unexplored tumor-intrinsic pathways.

This interdisciplinary proposal functionally dissects one particular tumor cell-expressed ICR and its undiscovered roles in cancer progression. As our seminal data reveals that it powerfully regulates cancer growth and metastasis, this research lays the groundwork for developing innovative drugs to block cancer advancement. Results will not only raise awareness of unanticipated impact of ICR drugs on a new tumor-intrinsic pathway but also invite further scientific and therapeutic inquiry and exploitation of this undefined pathway in cancer.

Philip Kranzusch, Ph.D.

Abeloff V Scholar*

A new form of treatment for cancer is to activate a patient’s own immune system to recognize and destroy tumor cells. Called cancer immunotherapy, this strategy has proven to have a remarkable impact on long-term survival for patients with a wide range of cancer types, but only a subset of individuals has sustained responses that can lead to a long-term cure. In order to advance cancer immunotherapy, it is critical to understand the immune signals responsible for robust tumor immunity.

One key part of the immune response to cancer is a cellular protein named STING (Stimulator of Interferon Genes) that allows immune cells to detect DNA derived from tumors. STING naturally responds to drug-like small molecules, and an exciting new area of study is the idea of “STINGing cancer” – using compounds that specifically activate STING to boost tumor recognition and patient responses to cancer immunotherapy. In spite of the clear role of STING in immune cell responses, STING signaling is poorly understood and we do not understand how signaling leads to improved patient responses.

Our research will determine how STING transmits signals to the immune system and which STING signal is critical for combating cancer. These experiments will provide the foundation for the design of next-generation drugs that target STING and, ultimately, will help us understand how to use cellular proteins like STING to better control human immune responses and treat cancer.

Michael Birnbaum, Ph.D.

Scientists have recently made tremendous progress in treating cancers by activating the immune system to attack the tumor. However, these therapies are not effective against cancers with less DNA damage due to insufficient anti-tumor immune responses. The immune system is capable of attacking these tumors, but suppressive immune subtypes such as regulatory T cells (Tregs) are coopted by the tumor to protect itself. Tregs are associated with poor survival in many cancers, and show enrichment for particular T cell receptors (TCR). The TCR senses targets by binding to their peptide-MHC ligands, which display a cross-section of peptides expressed by a particular cell. Despite their important role in protecting tumors, the identity and specificity of tumor-resident Tregs is poorly studied.  We are working to profile what T cells are enriched in low mutation rate cancers. We can then use approaches we have developed to find what these T cells as seeing in the tumor. This information will help us understand of one of the most important tumor-protective cell types, and may open the door to new cancer immunotherapies. 

Alejandro Gutierrez, M.D.

Funded by the Dick Vitale Gala, in memory of Benji Gilkey

T-cell acute lymphoblastic leukemia is an aggressive cancer that is most common in teenagers.  Many patients cannot be cured, even with intensive chemotherapy.  Our goals are to understand why chemotherapy does not cure some patients, and use this knowledge to improve treatment.  We found that chemotherapy cannot cure patients whose leukemia cells are very difficult to kill in a test called BH3 profiling.  This proposal is focused on mutations of a gene called JAK3 as a cause of death resistance of leukemia cells.  This idea could be immediately translated into a clinical trial because JAK3-blocking drugs are already FDA-approved for clinical use.  Here, we will ask the following questions:  1) Do JAK3 mutations block cell death in leukemia cells?  2) Will a JAK3-blocking drug improve the effectiveness of chemotherapy?  3) Is a JAK3-blocking drug safe and effective for the treatment of children with T-cell acute lymphoblastic leukemia?  Successful completion of this project could lead to more effective treatment options for children with this particularly high-risk subset of T-cell leukemia.

Timothy Graubert, M.D.

2017 V Foundation Wine Celebration Vintner Grant in honor of David and Kary Duncan

Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are blood cancers diagnosed in approximately 25,000 and 19,000 individuals each year in the US, respectively. Despite an enormous global effort, the treatments and outcomes for patients with MDS and AML have not improved significantly over the past 4 decades. The purpose of this study is to evaluate a new idea for MDS/AML therapy to see if there is sufficient promise to launch a clinical trial for patients at our center.

By studying the genomes (the DNA blueprint in all cells) of patients with MDS/AML, the scientists involved in this proposal identified mutations (“mistakes”) in a structure called the spliceosome. These spliceosome mutations are very common in patients with MDS/AML. We recently found that the spliceosome-mutant cells are more readily killed in the laboratory by two drugs that are currently being tested in clinical trials for other cancers.

In this project, we will test these two drugs alone and in combination using systems that we have developed in the laboratory. We will determine how, at the molecular level, these drugs kill the spliceosome-mutant cells and how they may become resistant to these treatments. Finally, we will develop tests to monitor the effects of these drugs when given to patients with MDS/AML. Since these drugs are already in clinical development for other indications, we expect that our work will rapidly help lay the foundation for clinical trials to see if these drugs offer new hope for patients with MDS and AML.