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.
Few procedures are available for physicians to rapidly and reliably harness immune responses to fight cancer. For example, bioinformatics tools can predict cancer proteins that T cells could react with, but vaccines developed from them commonly fail because the immunized patients do not have enough T cells that are inherently able to recognize the predicted antigens.
The goal of our research is to develop injectable nanoreagents that can genetically program T cell receptors (TCRs) into circulating lymphocytes, enabling them to recognize cancer proteins. Specifically, we hypothesize that customized cancer-targeting can be introduced into immune cells by combining anti-cancer vaccines with techniques that induce endogenous CD8 T cells to express TCRs specific for the vaccines, and consequently provide them with the ability to react with cancer cells. We further hypothesize that this platform can be used to program helper cells with defined “MHC class-II-restricted TCRs”, and thereby improve responses to tumor antigens compared to conventional immunization methods.
Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that injected nanoparticles can deliver engineered TCR genes into host T cells in a way that, once they are stimulated by vaccines, the lymphocytes recognize cancer antigens. Following rapid vaccine-induced expansion, these programmed cells continue to differentiate into long-lived memory T lymphocytes.
We propose to develop a suite of nanoparticle reagents that can rapidly establish anti-cancer immunity by programming in situ specific receptors into the patient’s T cell pool. To achieve this, we will pursue the following Specific Aims:
(1) to improve our efficiency for introducing vaccine specificity into circulating CD8+ T cells; (2) to establish that this approach boosts immune responses; and (3) to determine if our methods promote the regression of cancer regardless of the patient’s pre-existing TCR landscape.
To assure the medical relevance of our findings, we will (i) program the lymphocytes to express an affinity-optimized receptor specific for the tumor antigen mesothelin, and (ii) use them to treat a genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma from inception to invasion.
We believe that the data, reagents, and application methods generated by our research will provide the basis for a broad repertoire of gene modification systems that can generate selective immunity against cancer and other diseases.
Patients with metastatic synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCL) urgently need better treatment options. Therapies that employ anti-cancer immune T cells are proving effective against certain other malignancies, and SS and MRCL are ideal targets for this very promising approach. Both sarcoma types consistently express the NY-ESO-1 protein (AKA: antigen).
Our group and others have shown that NY-ESO-1-specific T cells can attack SS and MRCL tumors in patients, but we need to further improve this therapy to produce more consistent, complete and durable responses. Most T cell therapies use CD8+ T cells, but CD4+ T cells might also be critical for effective treatment of these diseases. CD4+ T cells directly support CD8+ T cells and activate the ‘antigen-presenting’ cells (APC) that help CD8+ cells recognize tumor antigens.
We can genetically engineer T cells to recognize NY-ESO-1 by engineering them to express a T cell receptor (TCR). We isolated the genes for two highly active TCRs specific for NY-ESO-1, one to be used in CD4+ cells and one to be used in CD8+ T cells. These TCRs were discovered in a very unique way, by using mice that had been engineered to have human immune system components. We are now ready, for the first time, to combine both genetically engineered CD4+ and CD8+ T cells.
We will also precisely irradiate tumors to damage them and help our infused T cells recognize the tumor. We propose a first-in-human, first-in-class clinical trial for SS and MRCL patients addressing a fundamental question in cancer immunotherapy, i.e., are both CD8+ and CD4+ T-cell functions necessary for optimal response? This trial will evaluate the safety and efficacy of the engineered T cells and using biopsy samples, we will analyze the changes that occur in the tumor following the treatment.
If successful, the proposed studies could transform the treatment paradigm for patients with SS and MRCL and address fundamental questions in immunology, potentially advancing novel strategies that can broadly improve immunotherapy efficacy and patient outcomes.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Wendy Walk.
