Development of CA-IL-12 for Triple Negative Breast Cancer
NIH
CYTONUS THERAPEUTICS, INC.
Most cancer patients die as a result of metastatic disease and our inability to effectively deliver therapeutic drugs into the anatomical niches where cancer cells thrive. Thus, there is a major unmet need to develop therapeutic strategies that effectively target cancer cells in the local tumor microenvironment (TME) while minimizing peripheral toxicity. Cytonus Therapeutics and UCSD Moores Cancer Center has co-developed a highly innovative first-in-class drug transporter platform (CargocytesTM) that is a safe and effective means to deliver therapeutic drugs to treat primary and secondary tumors. Cargocytes possess several unique features that we leverage for precision delivery of cancer therapeutics to patients with metastatic disease. First, Cargocytes possess innate tumor trophic properties and are engineered with additional homing controls that allow for precise, predictable, and safe delivery of therapeutic cargo to the TME. Moreover, because they lack a rigid nucleus, they clear critical FDA barriers to safety due to their inability to transfer or inappropriately express genomic DNA. In addition, they are smaller and more malleable than nucleated carriers and better able to penetrate deep within tumor tissue and metastatic foci. Furthermore, they retain all biosynthetic machinery and can express biological cargo within the TME. While Cargocytes can deliver a wide range of therapeutic cargoes, they are ideally suited for locally delivering potent immune activating agents, such as IL-12, into the immunologically “cold” TME. Our phase I proof-of-concept work shows that Cargocytes precisely deliver IL-12 into the TME, deeply penetrating and interdigitating within metastatic foci when delivered intratumorally or systemically and resulting in a dramatic reduction in metastatic burden that can be measured within 24 hours. While this was demonstrated using Cargocytes that secrete IL-12 (CA-IL-12), we have since focused on development of Cargocytes for intravenous delivery, a more desirable administration route for clinical development and treatment of systemic metastatic disease. Therefore, Phase II work will evaluate the potential of intravenously administered Cargocytes to deliver secreted (CA-IL-12) or surface contained (CA-scIL-12) to breast cancers that have metastasized to lungs or liver. Our hypothesis is that Cargocytes will home to metastases, deliver IL-12 deep within disease foci, and break immune tolerance when used in combination with ICB. This will lead to i) local and systemic antitumor immunity, ii) a reduction in metastatic burden, iii) improved tumor-free and overall survival, and iv) durable antitumor immunity. Three specific aims are outlined to test this hypothesis. Aim 1 will determine the abilities of peripherally administered CA-scIL-12 and CA-IL-12 to locally deliver IL-12 to primary and secondary tumors and to reprogram innate and adaptive anti-tumor immune responses. Aim 2 will then evaluate the ability of our lead CA-IL-12 medicine selected in aim 1 (CA-IL-12L) in combination with PD-1 antibody in the adjuvant setting to effectively treat ICB refractory tumors and generate systemic antitumor and antimetastatic immunity. Aim 3 will test the therapeutic efficacy of CA-IL-12L and ICB in a robust preclinical model of spontaneous breast oncogenesis that preserves tumor heterogeneity. Narrative. Cancer is a systemic disease and conventional treatment strategies that are administered systemically, ultimately fail due to an inability to achieve antitumor efficacy at tolerable doses for the patient. Cytonus has developed a first-in-class, precision delivery platform, called CargocytesTM, that is a safe and effective means to target therapeutic drugs to primary and secondary tumors. In this phase II study, we will evaluate the therapeutic efficacy of systemically-delivered, locally-active, membrane-tethered or secreted IL-12 to induce durable systemic antitumor and antimetastatic immunity.
SBIR/STTR