The University of Melbourne
Project Term: July 1, 2022 - June 30, 2025
Despite the promise of CAR-T cell immunotherapy for patients with lymphoma and multiple myeloma, a significant proportion of patients fail to respond or relapse following treatment. This project will focus on the clinical translation of a new treatment designed to improve durable response rates by combining CAR-T cell therapy with a new class of anticancer drugs called SMAC-mimetics. The results will provide the evidence base to drive a first-in-human clinical trial of this combination strategy.
This proposal centres around a promising new treatment for blood cancers using Chimeric Antigen Receptor (CAR)-T cell therapy combined with a class of anti-cancer drugs called SMAC-mimetics. CAR-T cell therapy involves the genetic modification of a patient’s immune cells to generate a pool of T cells equipped to specifically recognize and kill cancer cells when infused back into the patient. This immunotherapy has shown impressive results in the treatment of paediatric patients with acute lymphocytic leukemia, but the success rates for patients with other blood cancers, such as aggressive lymphoma and multiple myeloma (MM), are less impressive. Strategies to improve response rates and durability through the incorporation of therapies that boost the activity of the CAR-T cells and prevent relapse are needed to increase the number of patients that benefit from this therapy. We have promising preclinical data to suggest that SMAC-mimetics will enhance CAR-T cell efficacy and in this project we will investigate the translation of this combination for aggressive lymphoma and MM, where CAR-T cell therapy is most advanced.
In aim 1 we will use suite of laboratory assays to elucidate how SMAC-mimetics promote CAR-T cell proliferation and survival. As one caveat to the success of CAR-T cell therapy is poor survival of the T cells once transferred into patients, combining a SMAC-mimetic with CAR-T cell therapy presents an exciting opportunity to overcome this key limitation by promoting T cell expansion and survival in patients. We will also test the ability of SMAC-mimetics to enhance CAR-T cell activity against CD19-expressing lymphoma cell lines and BCMA-expressing MM cell lines using a suite of T cell-tumor cell assays that measure the interactions and killing of the cancer cells. The sensitivity to cell death by CAR-T cell and SMAC-mimetic treatment will be correlated with genetic analyses of the tumor cells to identify which patients will benefit from this therapy.
In aim 2 the combination therapy will be assessed using preclinical mouse models of lymphoma and multiple myeloma. These experiments will define the optimal timing of the introduction of the drug relative to the CAR-T cell infusion. To re-create a model that more closely mimics the human disease, these studies will use a novel humanised mouse model of MM, engrafted with human immune cells and MM cells from the same patient to test anti-BCMA CAR-T cell persistence and anti-tumor efficacy in combination with a SMAC-mimetic.
We will design a clinical trial based on the preclinical data from this study to incorporate a SMAC-mimetic into CAR-T cell therapy for lymphoma and multiple myeloma if this combination therapy proves safe and effective in our preclinical models as expected. This combination incorporates two treatment modalities currently approved or in clinical trials, so the identification of improved durability of response can be accelerated into the clinic very rapidly.