Enhancing Renal Cell Carcinoma Immunotherapy with Neoepitope Vaccination Strategies
Abstract
One of the most intriguing recent approaches to cancer treatments is the targeting of neoepitopes; that is, mutations specific to the tumor cells that can be targeted and eliminated by the immune system. This type of emerging immunotherapy could prove useful for kidney cancer, as this disease has historically been at the forefront of cancer immunotherapies including high-dose interleukin-2 (U.S. Food and Drug Administration FDA approval in 1992) and immune checkpoint blockade (ICB; FDA approval in 2015). ICB is now a frontline therapy for kidney cancer and aims for restoration of cytotoxic T cell function. One exciting concept in this regard is, therefore, to make a vaccine that trains cytotoxic T cells to target kidney cancer neoepitopes. At the present time, next-generation sequencing can easily identify the neoepitopes within a tumor, but the challenge is that few, if any, of these result in functional immunogenic responses. The main problem is, therefore, finding which neoepitopes are immunogenic. To address this, we have developed a potent, next-generation vaccine platform that enables induction of neoepitope-specific cytotoxic T cells with orders of magnitude greater potency relative to other vaccine adjuvants. This also allows unprecedented multiplexing (i.e., 60 peptides at once), which can be used to identify those rare immunogenic neoepitopes. Our approach is enabled by a next-generation vaccine adjuvant system that involves cobalt porphyrin-phospholipid (CoPoP), which was discovered by our laboratory and which induces rapid particle formation of short neoepitope candidates for ultrapotent immune responses. CoPoP has recently completed phase 1/2 human clinical trials as a component of a COVID-19 vaccine (Clinical trials identifier #: NCT04783311) and is in planning for a phase 3 trial. We found that CoPoP can also be used to induce ultrapotent neoepitope-specific cytotoxic T cell responses in mice for short synthetic MHC-I restricted epitopes for antitumor responses. To do so, we used next-generation sequencing to identify mutations in a particular mouse kidney tumor model, which is widely used in kidney cancer research. As the first working neoepitope ever discovered in a preclinical kidney cancer model, this speaks to the power of the CoPoP system. We will explore how to optimize this promising approach and also apply it to human kidney cancers from de-identified samples from patients in Buffalo. Specific Aims and Study Design: Enhance the frequency of neoepitope-specific functional neoepitopes cancer vaccines. We will assess various parameters of the CoPoP peptide particle vaccine system, including antigen density, the concentration of immunostimulatory molecules, and the amount of multiplexing that is possible Determine how neoepitope vaccination strategies enhance ICB immunotherapy. Various ICB antibody treatment regimens will be combined with neoepitope immunization to advanced tumors in the mouse kidney cancer model. Different types of antibodies will be assessed, as will the timing of ICB and vaccination. In vitro assessment of tumor cell lysis with ICB and neoepitope-specific cytotoxic T cell lymphocytes will be assessed. Apply the vaccine system to human kidney cancer neoepitopes. To advance this promising technology toward human application, we will obtain the tumor samples from 3-4 kidney cancer patients in Buffalo. Neoepitopes will be identified with next-generation sequencing. A unqiue mouse model developed by co-investigator Dr. Mori Tsuji at Columbia University that has a humanized immune system (HIS) mouse model will be used to then test the neoepitope candidates to determine which of the most promising are actually immunogenic. Altogether, the proposed studies will pave the way to bring this potent neoepitope vaccination approach into clinical trials for kidney cancer patients. The FY21 KCRP Focus Area is Develop novel therapeutic strategies for the t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210562
Entities
People
- Jonathan F. Lovell
Organizations
- United States Army
- University at Buffalo