Novel Antibody-drug Conjugates for Gamma-Delta T-cell Cancers

About This Grant

Project Summary Gamma-delta T-cell leukemias and lymphomas (GD T-cell cancers), affect ~1000 patients in the United States each year. Patients with GD T-cell cancers respond poorly to chemotherapies, with some patients experiencing a median survival of only 10 to 15 months. Significant challenges in improving survival for these patients are our poor understanding of the genomic mutations that drive GD T-cell cancers and our inability to selectively kill the GD T-cell cancer cells without harming the normal cells. Recent studies performed by multiple groups including ours have identified genomic mutations in critical signaling pathways that converge on the oncogene MYC. MYC is required for cell proliferation and survival in normal cells and increased MYC activity has been linked to the development of multiple solid cancers. Thus, we surmise that the mutations observed in GD T-cell cancers lead to an overactive MYC signaling which may be driving tumorigenesis in GD T-cell cancers. In addition, we postulate that selective inhibition of MYC activity in GD T-cell cancers will kill the cancer cells without harming the normal cells. For Aim 1, we propose to establish a mechanistic link between the genomic alterations observed in GD T-cell cancers and MYC-driven oncogenesis. We will engineer the mutations in normal cells and quantify how these changes lead to increased MYC activity leading to increased cell proliferation that ultimately leads to cancer. To selectively deliver drugs to block MYC activity in GD T-cell cancers, we developed an antibody that targets the GD T-cell receptor, which is only expressed in GD T-cell cancers and normal GD T cells. We coupled the antibody with drugs that block MYC activity and demonstrated that the antibody-drug conjugate (anti-GD ADC) selectively blocks MYC, leading to the death of cancer cells and normal GD T cells. We previously used similar methods to generate ADC to target other T-cell cancers and the ADC is scheduled to enter a phase 1 clinical trial (Nichakawade et al., Nature 2024). As normal GD T cells are a minor percentage (~5%) of immune cells, their loss is expected to be well tolerated in patients. For Aim 2, we will test the anti-GD ADCs in mouse models that closely resemble the human GD T-cell cancers. However, as such mouse models are currently unavailable, we will implant patient-derived and cell line-derived GD T-cell cancers in mice to closely replicate the diverse phenotypes and genomic profiles of GD T-cell cancers observed in patients. We will then test the safety and efficacy of the anti-GD ADCs in our mouse models. Lastly, most cancers treated with ADCs tend to develop resistance leading to cancer relapse. Thus, for Aim 3, we will identify possible resistance mechanisms that may develop in cancer cells to our anti-GD ADCs. We will then generate methods to counter the resistance and test the methods in our mouse models. Our studies aim to establish the mechanism by which normal GD T cells turn into cancer cells. In addition, the studies will provide the pre-clinical validation required to initiate a clinical trial of anti-GD ADCs and may improve the survival of patients with GD T-cell cancers.