Immunotherapy is an effective treatment for patients with certain types of cancer. These innovative treatments use the patient’s immune system to fight off cancer cells. T cells of the immune system are potent pathogen killers and maintain memory to provide long-term protection. We reprogram cancer patients’ T cells to find and kill cancer cells, but not healthy tissue, by expressing a chimeric antigen receptor (CAR) that will bind to tumor-specific antigens on the cancer cell.
The goal of our lab is to improve CAR T cell therapy by making them more effective in killing cancer cells and/or preventing the toxicities associated with treatment.
Our current projects focus on three areas of CAR T cell research.
1. Improving CAR T cell efficacy and expanding their use to other tumor types.
2. Developing CAR T cells that are safer for patients.
3. Understanding the basic biology of CAR T cell function.
Improving CAR T cell efficacy and expanding their use to other tumor types.
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The CAR T cells approved for use by the FDA target CD19 and B cell maturation antigen (BCMA), antigens found on normal and malignant B cells and plasma cells. These CAR T cells work well for treating B cell leukemia and lymphomas and multiple myeloma, but patients can still relapse with antigen negative disease, and they do not work for hematologic malignancies that lack CD19 or BCMA expression. CAR T cells have also been less successful in solid tumors, due to the difficulty in identifying tumor-specific target antigens that will not lead to toxicities, suppression by the tumor microenvironment, and mechanisms of resistance used by the cancer cells.
Our lab is working to develop CAR T cells that target other or additional antigens to improve tumor cell targeting and expand the use of CAR T cells to other tumor types. We have developed CAR T cells targeting a novel antigen, CD37, in B and T cell leukemia and lymphoma; used a natural ligand of BCMA and TACI in its trimeric form, named TriPRIL, to improve CAR T cell targeting of multiple myeloma; engineered EGFRvIII targeting CAR T cells to secrete a T cell engaging molecule (TEAM) that binds EGFR on the tumor cell and CD3 on T cells, named CARv3-TEAM-E, to increase tumor killing in Glioblastoma; and combined a novel target antigen, CD79b, with CD19 in a tandem CAR to improve CAR T cell efficacy in B cell leukemia and lymphomas.
Developing CAR T cells that are safer for patients.
Though CAR T cells work well in some patients, most patients experience toxicity with CAR T cell treatment. These toxicities are caused by the activation of T cells leading to recruitment and activation of other immune cells, which release cytokines and cause inflammation. One way to prevent toxicity is to limit when the T cells are activated (turned “on”), or not (turned “off”). To readily control CAR T cell activation, we have designed CAR T cells with a zinc finger degron tag, that when treated with the drug lenalidomide will degrade the CAR, thereby turning the CAR T cell “off”. Alternatively, the extracellular and intracellular portions of the CAR can be split between two proteins that will only interact in the presence of lenalidomide, thereby controlling when the CAR is turned “on”. We hypothesize that limiting CAR T cell activation will prevent toxicity.
Jan et al, Sci Transl Med 2021
Understanding the basic biology of CAR T cell function.
Boroughs et al, Mol Ther 2020
To make better CAR T cells, we also need to understand exactly how they function. By studying the interactions CAR T cells have with tumor cells and the pathways they use to become activated and kill tumor cells (versus the pathways used by regular T cells), we can better engineer CAR T cells for optimal efficacy. One way we have done this is to understand the role that varying intracellular signaling domains play in CAR T cell activation, persistence, and phenotype. Most CAR T cells contain either a 4-1BB or CD28 costimulatory domain and the CD3zeta activation domain as their intracellular signaling components. By closely comparing CAR T with 4-1BB vs CD28 costimulatory domains, we found these domains uniquely shape the transcriptional program of the T cells, which relates to their function in patients. The knowledge gained from this analysis will help us better design CAR T cells that will work optimally in patients.
Clinical trials with CAR T cells targeting novel antigens
Since the Maus lab formed in 2015, we have translated several of our novel CAR products to the clinic. Currently, we have two open clinical trials with products we developed and two that are in the process of being initiated.
R/R, relapsed/refractory; IND, investigational new drug application
Clinical trials to improve the safety of CAR T cells
We also have initiated a clinical trial to treat patients receiving CD19 CAR T cells prophylactically with anakinra to prevent toxicities from developing. CAR T toxicities occur when T cell overactivation leads to the release of inflammatory cytokines, which activate macrophages to release additional cytokines. Current treatments to manage toxicity include targeting IL-6 (with tocilizumab), a cytokine increased during CAR T cell toxicity, or using steroids to dampen inflammation. While tocilizumab effectively treats cytokine release syndrome, it is not effective for neurotoxicity. Neurotoxicity is usually treated with high dose steroids, but this can decrease CAR T cell expansion, thereby limiting their efficacy. However, anakinra targets a cytokine upstream of IL-6 (IL-1) and may prevent toxicity without affecting CAR T cell function. Therefore, we are treating patients with anakinra during the first few days following CAR T cell injection and determining if anakinra prevents toxicities from occurring.
Axi-cel, axicabtagene ciloleucel; R/R, relapsed refractory
Clinical trials in novel tumor types
Another way to improve CAR T therapy is to use the currently approved products for novel patient populations. Patients with primary CNS lymphoma were excluded from treatment with the approved CAR T cell therapies due to the risk of toxicities. However, as toxicity management strategies for CAR T cell patients have improved, it may be possible to safely treat these patients. Dr. Matthew Frigault, an alumnus of the Maus lab and Clinical Director of the Cellular Immunotherapy Program, has initiated a clinical trial of tisagenlecleucel, one of the CD19 targeting CAR T cells, for this patient population. These efforts will increase the use of CAR T therapy to improve outcomes for a wider range of patients.
Tisa-cel, tisagenlecleucel; CNS, central nervous system
Our phase I studies will demonstrate the safety of our cellular therapy products in patients, and may provide preliminary efficacy data, but they also provide us with important information on how the CAR T cells behave in patients. Through correlative studies of patient blood and tumor samples throughout the course of their treatment, we can determine how each unique product engrafts, expands, persists, localizes, and functions. This information allows us to understand why a product is (or is not) safe and effective in these patients. Using this knowledge, we can strategically engineer the next generation of CAR T cells that will be safer and more effective in patients. The clinical trial correlative studies are performed by the Immune Monitoring Lab (IML), which is directed by Dr. Kathleen Gallagher.
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