ACGT – Edward Netter Memorial Investigator Award in Cell and Gene Therapy Research for Pancreatic Cancer
Cell-based therapies for cancer have been highly successful in blood cancers such as leukemia and lymphoma. These therapies take the form of chimeric antigen receptor T cells (CAR T cells), which recognize and kill cancer cells. However, translating these therapeutic successes to cancers of internal organs – tumors of the lung, breast, colon, etc. – has been challenging. A major reason for this difficulty is that these “solid tumors” are protected by layers of protein and cells that shield the cancer from immune attack. This barrier to anti-tumor immunity is called the tumor microenvironment (TME), and pancreatic cancer represents the most extreme case of this impermeability. Our proposal seeks to disrupt this obstacle so that CAR T cells may gain entry to the tumor and exert their anti-cancer activity.
Our strategy contains two approaches. The first involves KRAS – a cancer-causing mutant protein that is the source of over 90% of pancreatic cancers. Recent advances in drug development have resulted in several chemical inhibitors of KRAS with dramatic anti-cancer effects in animal models and patients (leading already to FDA approvals in certain cancers). KRAS inhibitors exert most of their activity by killing cancer cells. However, a fortuitous side benefit is that these drugs also reshape the TME to allow immune cells (especially T cells) to infiltrate tumors. Our preliminary data in mice demonstrate that treatment with a KRAS inhibitor allows more T cells (including CAR T cells) to enter the tumor, resulting in greater anti-cancer activity. Our second approach involves the use of CAR T cells directed against a component of the tumor barrier – fibroblast activation protein (FAP). We have shown that CAR T targeting FAP can force their way into tumors, bringing other T cells (including other CAR T cells) along with them. As a result, combinations of anti-FAP CAR T cells with either chemotherapy or cancer-targeted CAR T leads to greater anti-tumor effects.
Our proposal includes studies in both animals and patients. Aim 1 extends our work on KRAS inhibitors and FAP CAR T cells in mouse models to understand how these interventions reshape the TME. We will also determine whether combining the two therapies can have additive effects, leading to cures (as suggested by our preliminary studies). Aims 2 and 3 focus on patients. Aim 2 builds on an ongoing clinical trial in pancreatic cancer of CAR T cells against mesothelin. Our goal is to determine whether pretreatment with a KRAS inhibitor before CAR T infusion results in a greater number of CAR T cells inside the tumor. Aim 3 involves a clinical trial of FAP CAR T cells scheduled for 2025 in which we will assess whether these CAR T cells penetrate patient tumors (as they do in our animal models) and reshape the TME in a favorable manner.
Collectively, these studies aim to break down the physical and immunological barriers limiting the efficacy of CAR T cell therapy for pancreatic cancer.
ACGT – Edward Netter Memorial Investigator Award in Cell and Gene Therapy for Pancreatic Cancer Research
Patients with pancreatic cancer (PDA) generally present with advanced disease, and standard treatment regimens have provided limited benefit in this setting. Immunotherapy has proven to be a promising new therapy for many malignancies, but yielded only marginal benefit thus far in PDA. We have pursued a strategy for engineering immune cells to be able to recognize tumors, and then administering large numbers of these cells to treat cancers. We demonstrated in a mouse model that CD8 T cells engineered with a tumor-specific T cell receptor (TCR) targeting the tumor antigen Mesothelin can infiltrate pancreatic tumors and mediate therapeutic anti-tumor activity.
This led to a clinical trial in which patients with metastatic PDA were treated with their own CD8 T cells that we engineered ex vivo with a human MesotheIin-specific TCR. Biopsies were obtained after T cell infusions, infiltrating T cells isolated, and the T cells and tumor cells analyzed in depth to elucidate obstacles to efficacy. In both the mouse model and clinical trial, the infused CD8 T cells by day 21 had acquired in the tumor characteristics of exhaustion, becoming dysfunctional and failing to expand at the tumor site. Therefore, we have been developing synthetic strategies for further engineering of T cells to enhance activity for mediating more sustained responses.
For this trial, we have isolated a human TCR specific for mutated KRAS, which in the vast majority of PDA cases is an obligate driver of the cancer, making it difficult for the tumor to evade responses by losing the antigen. To better sustain T cell responses, we are introducing the TCR plus CD8 genes, which improve TCR binding to its target, into both CD4 and CD8 T cells to create a coordinated T cell response in which both CD4 and CD8 T cells can recognize and respond to the same and adjacent tumor cells. These genes can now create functional CD4 T cells, which has been shown in multiple models to not only promote CD8 T cell function, proliferation, and survival, but also delay or prevent exhaustion. Therefore, in this clinical trial for advanced PDA we will treat patients with their own CD4 and CD8 T cells engineered to express both a TCR specific for mutant KRAS and the CD8 genes.
Patients will be biopsied before and after T cell infusions, as our prior experiences highlighted the value of in-depth analysis of the tumor and infiltrating T cells to elucidate reasons for success or failure for building next generation strategies. The high dimensional data will be used to engineer T cells that can overcome encountered obstacles impeding tumor eradication and will be validated in preclinical PDA models. We have already generated synthetic proteins that can convert inhibitory or death signals into costimulatory and survival signals, or suppressive signals into proliferative signals, and will prioritize advancing to next generation trials the synthetic strategy(s) most effective for overcoming observed obstacles.
