Combining Locally Administered Ipilimumab with a Personalized Neoantigen Cancer Vaccine to Improve T-Cell Priming and Antitumor Immunity in High-Risk Renal Cell Carcinoma
Abstract
Kidney cancer is a common cancer in both the general and the Veteran population, and is responsible for nearly 15,000 deaths each year in the United States. Nearly one-third of patients have advanced disease at the time of diagnosis, and an additional 30% of patients with earlier stage disease will go on to develop advanced disease even after surgery to remove all visible tumor. While there have been many new therapies for kidney cancer, only 8% to 12% of patients with advanced kidney cancer live for 5 years or longer. Over the past few years, a new type of therapy called immune checkpoint blockade (or "ICB") has shown tremendous promise in the treatment of kidney cancer. These therapies work by "cutting the brakes" on the immune system, with the hope that the patient s immune system will then be able to recognize and eliminate kidney cancer cells in the body. While exciting, the majority of patients do not respond (i.e., tumors do not shrink), and many patients experience severe side effects from an overactive immune system. This may, in part, be due to the non-specific way these drugs work -- they cut the brakes, but do not steer the immune system to specifically fight the cancer cells. Moving forward, a fundamental challenge is how to steer the immune system to specifically attack the cancer cells, both to improve how well these immune therapies work, and to decrease the number of side effects. A set of recently completed clinical trials in melanoma (a type of skin cancer) and glioblastoma multiforme (an aggressive form of brain cancer) trail-blazed the idea that a personalized vaccine could drive the immune system to directly target proteins on the surface of cancer cells (generated by patient-specific cancer mutations, called "tumor neoantigens"), but it also demonstrated a clear need to find new treatment combinations to improve the strength of the immune system s anti-cancer response. For the first time in patients with kidney cancer, we are studying the combined administration of a personalized anti-cancer ("neoantigen") vaccine. Each patient in this ongoing, actively enrolling trial has their own custom drug (vaccine) manufactured, based on each patient s specific cancer genomic data. In addition, this novel vaccine is combined together with skin injections of a powerful ICB (called Ipilimumab) in patients with high-risk kidney cancer, to test if this is an effective approach to augment the number and strength of vaccine-induced T cells. Our initial study includes patients with the most common subtype of kidney cancer ("clear cell"), who have advanced disease (stage III or stage IV), but have had all of the disease removed by surgery. These patients are at a very high risk of having their kidney cancer recur. Our clinical trial will help determine if this combination is safe (i.e., has few side effects) and, if so, what doses of Ipilimumab should be used for this combination. Importantly, the trial will also begin to look at the effectiveness of this novel, personalized immune therapy approach (i.e., does it reduce or prevent the cancer from coming back after surgery). Multiple patients are already enrolled in this ongoing trial, and the first patient has already completed the first portion of the vaccine treatment. However, in order to further develop this new therapy, it will be critical to study and understand why the personalized vaccine and ICB combination works for some patients, but does not work for other patients. In this grant proposal, we therefore aim to perform detailed studies of the immune system for patients participating in the clinical trial. Using state-of-the-art laboratory techniques, we plan to study the composition and function of immune cells in the skin, circulating in the blood, and in the tumor itself, which will allow us to understand the role that individual immune cells play in generating an anti-cancer response following vaccination. This grant will therefore b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010533
Entities
People
- Catherine Wu
Organizations
- Dana–Farber Cancer Institute
- United States Army