Novel drug for cancer immunotherapy that targets phosphatidylserine

Ended Project Grant Awarded Last action

Award ID
R43CA257721
Recipient
Awarding agency
Obligated
$879,529

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date
Funding
  • $586,351.22 Federal
  • $293,178.00 Non-federal
Place of performance
Eden, NY 14057, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Phosphatidylserine (PS) is emerging as an attractive immunotherapeutic target in the light of mounting evidence highlighting its causal link to immune suppression. We have established that exosomes derived from melanoma and ovarian tumor microenvironments express PS on their surfaces and suppress multiple activation endpoints of t cells triggered through the t cell receptor. Studies have also shown that expression of PS on the surface of many non-apoptotic cancer cells lead to immunosuppression. Recent clinical studies in melanoma patients demonstrated that exosomes that are released from patient tumors suppress t cell tumor killing and contribute to tumor progression. We have designed and synthesized a new compound, ZN-DPA)6-DP-15K (exoblock) that binds to phosphatidylserine with high avidity. Exoblock was shown to consistently and significantly block the immune suppressive activity of exosomes derived from melanoma and ovarian tumor microenvironments in vitro. Based upon these findings, we predicted that exoblock would enhance the killing of tumor cells by t cells in tumor xenografts due to its binding to PS on the exosomes, tumor and apoptotic cells, representing a multi- pronged approach. We tested this prediction using two different human tumor xenograft models: a) the previously validated in-house developed omental tumor xenograft (OTX) model established using patient-derived ovarian tumors, and b) the recently developed and validated xenomimetic mouse (x-mouse) model that allows US to quantify and establish the efficacy of multiple t cell-stimulating immune-based therapies pre-clinically. This model uses melanoma patient-derived tumor-specific t cells that are adoptively transferred into immunodeficient mice bearing melanoma xenografts expressing tumor NEO-antigens recognized by the t cells. The therapeutic efficacy of exoblock was next established by significantly enhancing tumor suppression in both the OTX and x- mouse models, and was found to be comparable to anti-PD-1 therapy in x-mouse model. Together, these results have laid the foundation and rationale for our work proposed in the phase i application. Additional toxicity and pharmacokinetic (PK) studies are proposed for exoblock in aim 1. The PK studies will help to determine the optimal dose, schedule and delivery method of exoblock that will be tested in aim 2. In aim 2 exoblock will be tested in vivo for its therapeutic efficacy in omental tumor xenograft (OTX) model consisting of patient-derived ovarian tumor and syngeneic mouse melanoma model with B16-F10 tumor. Our rationale for using both a human and mouse tumor model is discussed in the approach. The results of this phase 1 study will lay the foundation for a more extensive study in a future phase 2 study that will lead to an IND and clinical trial of exoblock.

Transactions

Action Federal Non-federal Date
Amendment -$5 $0
Amendment $293,178 $0
Original award $293,178 $293,178

Quick answers

Who received award R43CA257721?

R43CA257721 was awarded to Immune Modulatory Therapies LLC by National Cancer Institute (National Institutes of Health) on March 11, 2021.

How much is award R43CA257721 worth?

$879,529 has been obligated on R43CA257721: $586,351 in federal funding and $293,178 in non-federal funding.

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