Inhibition of RET Proto-Oncogene as Novel Immune-Based Strategy Against SCLC
Abstract
The Area(s) of Emphasis are to identify innovative strategies for the prevention of recurrence of or metastases from lung cancer and to identify innovative strategies for the treatment of lung cancer. SCLC is the most aggressive subtype among different lung cancers with a faster growth rate and late diagnosis with metastasis to other organs. The National Institute of Health, USA, has designated it a recalcitrant disease due to its ability to come back quickly after the first treatment with acquired resistance to other therapies. Recent clinical trials observed only marginal benefits from the addition of immunotherapy to chemotherapy. Immunotherapy activates the body’s T cells to identify and kill tumor cells. However, SCLC tumors developed a mechanism to suppress the tumor-killing activity of T cells by recruiting T cell suppressive monocytes and macrophage cells. A recent study showed that REarranged during Transfection kinase receptor (RET) is expressed on human peripheral blood mononuclear cells (PBMCs), including monocytes. Furthermore, activation of RET by its ligand induces the expression of various T cell suppressive molecules in PBMCs. We hypothesize that inhibition of RET will inhibit the monocyte cells that suppress T cells activity and thereby synergistically act with immunotherapy to enhance the anti-tumor T cell responses against SCLC. Pralsetinib is an orally bioactive and FDA-approved chemical inhibitor of RET and is being tested to treat non-small cell lung cancer in clinical trials. The overall objective of this proposal is to identify whether Pralsetinib can act synergistically with immunotherapy to exponentially enhance the anti-tumor T cell responses against SCLC by targeting T cell suppressive monocytic cells. In this proposal, we will isolate the monocytic cells from the mouse SCLC tumors and treat them with Pralsetinib or saline in a Petri plate. These treated cells will be evaluated for their ability to suppress T cell function in Petri plates. Next, we will replace mouse immune cells with human immune cells to generate humanized mice. These mice will be used to analyze the clinical utility of Pralsetinib alone or in combination with immunotherapy against SCLC in the mice injected with patient-derived tumor pieces. In the short term, these studies will provide novel information about the role of RET in T cell inhibition, which is often observed in SCLC. These studies will also define the preclinical potential of RET inhibitor alone or in combination with immunotherapy to inhibit SCLC. In the long term, these studies will provide valuable insight for the development of innovative combination therapy regimes against SCLC. The use of FDA-approved Pralsetinib will help in its quick transition from laboratory to clinic. Due to exposure to environmental carcinogens and tobacco smoking, lung cancer incidence is higher, and the survival rate is lower in military personnel than in civilians. A higher smoking rate is also known to affect T cell activities adversely. By developing novel immune-based therapies, these studies will have long-term effects for military personnel and beneficiaries suffering from deadly SCLC disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210038
Entities
People
- Dinesh Ahirwar
Organizations
- Ohio State University
- United States Army