Abstract
Integrase-defective lentiviral vectors (IDLVs) have been used as a safe and efficient delivery system in several immunization protocols in murine and non-human primate preclinical models as well as in recent clinical trials. In this work, we validated in preclinical murine models our vaccine platform based on IDLVs as delivery system for cancer immunotherapy. To evaluate the anti-tumor activity of our vaccine strategy we generated IDLV delivering ovalbumin (OVA) as a non-self-model antigen and TRP2 as a self-tumor associated antigen (TAA) of melanoma. Results demonstrated the ability of IDLVs to eradicate and/or controlling tumor growth after a single immunization in preventive and therapeutic approaches, using lymphoma and melanoma expressing OVA. Importantly, LV-TRP2 but not IDLV-TRP2 was able to break tolerance efficiently and prevent tumor growth of B16F10 melanoma cells. In order to improve the IDLV efficacy, the human homologue of murine TRP2 was used, showing the ability to break tolerance and control the tumor growth. These results validate the use of IDLV for cancer therapy.
Highlights
Cancer is the second leading cause of mortality worldwide, as reported by The WorldHealth Organization (WHO) with 9.6 million deaths in 2018
We and others previously demonstrated the strong efficiency of Integrase-defective lentiviral vectors (IDLVs) in inducing a potent and protective T cell immunity in different infectious disease models, including the HPV16 tumor model [29]
We further validated the IDLV-based platform for cancer immunotherapy, using different tumor models, starting survival of tumor bearing mice
Summary
Cancer is the second leading cause of mortality worldwide, as reported by The WorldHealth Organization (WHO) with 9.6 million deaths in 2018. The immunological tolerance represents a significant obstacle to be removed in order to obtain an efficient and comprehensive immune response against tumor antigens constituted by self-proteins (tumor associated antigens, TAAs). Different melanoma TAAs used in melanoma immunotherapy approaches include gp100, MART-1, and three enzymes associated with melanin synthesis, tyrosinase (tyr), tyrosinase related protein-1 and -2 (TRP1 and TRP2). These proteins have similar structures, but they are expressed by different genes and have different enzymatic activities. A recent paper suggests that TRP2 over-expression may be an important mediator of intrinsic drug resistance in melanoma cells [9]. Since TRP2 is located on plasma membrane, it can be considered as a target for ADCC activity [13,14]
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