Funded by the 2015 Wine Celebration Fund a Need, including donations raised by the Dick Vitale Gala and Bristol-Myers Squibb
Recent research revealed that malignant gliomas in children often have common gene mutations in a molecule named H3.3, which is a component of the human genome. Approximately 30% of pediatric glioblastoma and 70% of diffuse intrinsic pontine glioma (DIPG) cases have the same mutation which causes a change in the H3.3 protein. The human immune system, such as T-lymphocytes (T-cells hereafter), do not normally react to normal proteins, but can recognize and attack cells that have abnormal proteins. Therefore, cancer-specific mutations can be suitable targets for cancer immunotherapy, such as cancer vaccines and adoptive T-cell transfer therapy (i.e., infusion of large number of T-cells). Indeed, immunotherapy using patients’ own T-cells that are engineered to recognize cancer cells have shown remarkable success in other cancers, such as acute lymphocytic leukemia in children. However, it is also important to ensure that those T-cells attack tumor cells but not normal cells. We recently found that the common mutation in H3.3 includes cytotoxic T cells which can kill glioma cells that have the mutation but not cells without the mutation. We are proposing two lines of translational studies. First, we will isolate genes for the T cell receptor which allows the specific recognition of mutated glioma cells. This will lead to a near future development of adoptive transfer immunotherapy. Concurrently, we will design and conduct a pilot vaccine trial using synthetic peptide for the mutated part of H3.3 in children with H3.3-mutated DIPG or high-grade glioma.
The last two decades have seen the development of increasingly effective cancer therapies that target different facets of transformed cells, including aberrant proliferation/survival, immune evasion, hyper-activated signaling pathways and dysregulated transcriptional programs. In a subset of cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer with activating EGFR mutations, these therapies lead to dramatic clinical responses in a significant proportion of patients.
However, in the majority of AML and EGFR mutant lung cancer patients who respond to anti-cancer therapies, therapeutic relapse subsequently ensues, although often after a considerable interval, such that these responses do not lead to long-term cures. Often the relapsed tumors are infiltrated by adaptive immune cells (T cells). With the advances in immunotherapy, which utilize a patient’s own immune system to fight the cancer, it is possible to treat with immunotherapy after relapse. We are studying the T cell infiltrates before, during, and after relapse in both AML and NSCLC patients to determine if the response if the relapsed tumors have the characteristics of an immunogenic tum.
Tumors across different patients can be understood as independent evolutionary processes of clonal Darwinian evolution under distinct therapeutic evolutionary pressures. Different therapeutic strategies disrupt evolution in distinct ways allowing the inference of the order and co-mutation patterns specifically associated to these therapies. Inferring evolutionary patterns from large cross-sectional and longitudinal therapy specific cohorts will identify specific mechanisms of drug resistance, the genetic background of these mechanisms and will inform the dynamic model of the main routes of drug evasion.
First, using CAT(0) phylogenetic spaces, we will learn the statistics of phylogenetic processes associated specific drug mechanisms in breast cancer and melanoma. We conjecture that undisrupted evolutionary processes follow linear patterns and that specific therapies generate distinct branching patterns associated to number of alterations needed for relapse and effective size of the resistant population. Second, the highly branched processes associated to therapy allow to reconstruct the genetic alterations of ancestral clones allowing to order the genetic alterations. Combining cross-sectional information, one can elucidate the main routes of drug resistance, what alterations are selected under specific therapy and which is the mutational background in which they arise. As genomic data from clinical studies will be arriving we will generate first evolutionary models and integrate the results with the networks from dynamic modeling. By combining genomic data of longitudinal studies with state of the art network inference, we aim to uncover the main mechanisms of drug resistance and design combinatorial approaches.
Pancreatic ductal adenocarcinoma (PDAC) is a common and increasing cause of cancer death in the U.S.A. While attempts to harness the immune system to fight cancer has been successful in the treatment of many cancers, these strategies have to date been ineffective in PDAC. PDAC tumors contain not only cancer cells but a dense layer of fibrous tissue, called stroma. The stroma interferes with the immune systems ability to attack PDAC both by releasing substances that inhibit the immune system and by acting as a physical barrier to immune cells reaching the cancer cells. We have recently shown that Vitamin D can act on PDAC tumors to prevent the stroma from releasing immune inhibitory substances and to facilitate immune cell entry into tumors, potentially setting the stage for a more effective immune attack on PDAC. In this proposal, the post-doc/clinical fellow will work closely with a team of physicians, cancer immunologists, and computational biophysicists will work together to improve the effectiveness of immunotherapy for PDAC. The post-doc/clinical fellow will contribute toward the completion of two tightly coupled aims: first, novel theoretical and experimental tools will be used to characterize the patient-specific immunological environment of PDAC tumors; second, the detailed understanding of the immune environment in PDAC tumors will be used to develop novel immunotherapy strategies that will be tested in a new clinical trial. The clinical trial will use a combination of conventional chemotherapy, a potent Vitamin D analogue, a drug that activates immune cells, and surgery, in an effort to improve the outcomes of patients with pancreas cancer. The Penn post-doc will be the critical individual who supplies operative tissue to the diverse collaborators in the project, and correlates the different genomic and immunologic studies with patient outcomes. As such they will gain knowledge and experience in molecular phenotyping of tumors, immunotherapy, and clinical trials.
To provide the best experiences, we use technologies like cookies to store and/or access device information. Consenting to these technologies will allow us to process data such as browsing behavior or unique IDs on this site. Not consenting or withdrawing consent, may adversely affect certain features and functions.
Functional Always active
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
Preferences
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
Statistics
The technical storage or access that is used exclusively for statistical purposes.The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
Marketing
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.
To provide the best experiences, we use technologies like cookies to store and/or access device information. Consenting to these technologies will allow us to process data such as browsing behavior or unique IDs on this site. Not consenting or withdrawing consent, may adversely affect certain features and functions.
Functional Always active
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
Preferences
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
Statistics
The technical storage or access that is used exclusively for statistical purposes.The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
Marketing
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.
