Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy

Ut Southwestern Medical Center, Dallas TX

Investigators

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Abstract

Summary Malignant melanoma in advanced stages can be treated with immunotherapeutic antibodies that target CTL-4, PD1, and PDL1, resulting in enhanced survival rates. However, a large proportion of patients still do not respond to such therapies due to the presence of immunosuppressive signaling in the tumor microenvironment (TME). To generate an activated immune microenvironment, our laboratory has developed a liposome-based nanoparticle (NP) that upregulates calreticulin (CRT) in melanoma TME. Our in vitro and in vivo data in immunologically cold B16F10 melanoma suggest that intratumoral in-situ vaccination (ISV) with CRT-NP and its local combination with focused ultrasound (FUS) induce local and systemic immune priming, thereby resulting in a superior anti-tumor immunity. This is highly promising, but most preclinical studies including ours typically employ lean mice to investigate immunotherapeutic mechanisms. Risk factors like excess body weight can exacerbate tumor immunosuppression, but little is known about how CRT-NP efficacy is influenced by this mechanism, and whether the body mass index of patients should be taken into consideration for designing the phase I clinical trial. Herein, we will determine the CRT-NP, FUS, and CRT-NP+FUS (CFUS)-based ISV outcomes in the lean and obese murine models of melanoma. To test our objective, we will first compare the CFUS local efficacy and immune signaling mechanisms in the B16F10 model (Aim 1). Next, we will combine the mono- and CFUS therapies with immune checkpoint inhibitors in a clinically relevant YUMM1.7 murine melanoma (Aim2). The investigation of therapeutic and immune effects in lean and obese mice will enable the successful optimization of local CFUS in liberating tumors from their immune-suppressive state regardless of the physiological and metabolic status of the patients, thereby improving remission rates independent of cancer complexity. If successful, this method will provide a promising new avenue for treating melanoma and other types of solid tumors (e.g., breast, prostate) by significantly overcoming current immunotherapy barriers.