Wednesday, April 17, 2024
4/17/2024
PROJECT SUMMARY / ABSTRACT Non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy, and is divided into B-cell and T- cell lymphoma subtypes. B-cell NHL patient outcomes have improved dramatically with the development of new targeted therapies, but similar progress has not been made against peripheral T-cell (PTCL) and cutaneous T-cell (CTCL) lymphomas. Indeed, patients who relapse after initial PTCL therapy have a less than 1 year median survival, and patients with the CTCL subtype mycosis fungoides that is advanced, or that has Sézary syndrome with skin, blood, and lymph node disease, have a median survival of one year from diagnosis. Thus, the identification of novel targets and drugs with activity against PTCL and CTCL will be critical for this area of unmet medical need to help cure these diseases, which have not been a major focus for industry-sponsored research due to their heterogeneity and lower incidence. To address this challenge, we investigated the cell surface proteome of PTCL and CTCL cell lines and found Heat shock protein 70 (HSP70) to be highly expressed. Then, we developed monoclonal antibodies to human HSP70 and found that one, designated clone 239-87, recognized HSP70 on PTCL and CTCL cells but not on normal T-cells. To convert 239-87 into a drug, we linked it to monomethyl auristatin E (MMAE) to generate an antibody-drug conjugate (ADC), which we found inhibited PTCL and CTCL cell line growth as well as and, in some cases, better than brentuximab vedotin (BV), another ADC already approved for T-cell NHL. Also, 239-87-MMAE showed synergy when combined with other therapies already used against PTCL and CTCL, including the deacetylase inhibitor vorinostat and the ADC BV. Next, we used the 239-87 single chain variable fragment sequence to create chimeric antigen receptor (CAR) guided T-cells, and these were activated in the presence of T-cell NHL cell lines. Finally, in a cell line-based xenograft, the 239-87-MMAE ADC cured mice with an aggressive PTCL variant. Our preliminary data support the central hypothesis that targeting cell surface HSP70 using an ADC or CAR T-cell therapy approach will be both novel and effective against PTCL and CTCL, and could ultimately improve patient outcomes. In order to test this hypothesis, we propose three aims: (1) To investigate the differential expression of HSP70 in PTCL and CTCL models, including in primary patient samples, and to perform studies to identify pathways in these cancer cells that regulate HSP70 expression; (2) To identify the best ADC and CAR T-cell construct based on our 239-87 antibody, and explore which combinations will show greatest synergy; and (3) To use in vivo models, including patient-derived xenografts, to determine effective strategies against these lymphomas that will work best in the clinic. Taken together, successful completion of these studies will increase our understanding of the role of HSP70 in PTCL and CTCL biology, provide the rationale to take these approaches to the clinic for patients with PTCL and CTCL who are looking for novel therapies and, ultimately, improve their outcomes.
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