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UPenn Research Makes Landmark Strides in CAR T-Cell Cancer Immunotherapy

by Rachel DeRita, PhD candidate (Thomas Jefferson University, Department of Cancer Biology): Cancer immunotherapy is rapidly becoming one of the largest clinical and pre-clinical cancer research fields. You may even hear it talked about at your holiday cocktail party. In particular, the University of Pennsylvania has had a landmark year involving a particular type of immunotherapy, chimeric antigen receptor (CAR) T-cell therapy. This therapy involves taking a patient’s own T-cells and, outside the body, putting them through a cellular “boot camp” and training them to target a specific marker present on the cancer cell, but not normal cells. Those engineered T-cells are then administered back to the patient. Starting on August 30, 2017, the University of Pennsylvania (UPenn) and the Children’s Hospital of Philadelphia (CHOP) officially announced that the pioneering studies done at both institutions led to the first-ever cancer cell and gene therapy approval by the FDA. The approval was given to Novartis for Kymriah(TM) (formerly CTL019) to treat pediatric patients up to the age of 25 for B-cell precursor acute lymphoblastic leukemia (ALL). The T-cells in this therapy are primed and expanded to target cancer cells positive for a protein called CD19 present on the cancerous lymphocytes. Early-stage clinical trials observed more than 90% of patients achieving complete remission, leading to a global trial in 2015 that included 68 children and young adults with advanced ALL all over the world. After a single dose of their own engineered T-cells, a remarkable 83% of patients achieved complete remission. According to the investigators at UPenn’s Perelman School of Medicine and CHOP, in collaboration with Novartis, this marks a milestone for the treatment of younger patients with aggressive blood cancer. Specifically, Stephan Grupp, MD, PhD (the Yetta Deitch Novotny Professor of Pediatrics at Penn and Director of the Cancer Immunotherapy Frontier Program and Chief of the Section of Cell Therapy and Transplant at CHOP), declared that in larger trials overall remission rates of 80% are being observed, an improvement upon previous rates. The CEO of Novartis Oncology, Bruno Strigini, also expresses enthusiasm at the opportunity to provide pediatric patients with previously few options with renewed hope.

Additionally, other trials with CTL09 for adult ALL patients and non-Hodgkin lymphoma are currently being carried out. Other investigations into this technique are being carried out at UPenn for use in prostate cancer, melanoma, triple-negative breast cancer, multiple myeloma, glioblastoma, ovarian, and pancreatic cancer. UPenn made another announcement more recently on December 11th this year in regards to the progress made in UPenn trials of CAR T-cell therapy in other cancers, namely, non-Hodgkin Lymphoma (NHL). Stephen J. Schuster, MD, of UPenn’s Abramson Cancer Center led a pair of clinical trials sponsored by Novartis studying the use of Kymriah(TM) against NHL. In the first, global multi-site trial involving patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, 40% of patients had a partial or complete response at 3 months and 74% of those patients who responded remained cancer-free at 6 months. Eighty-one patients were infused and evaluated in this trial across 27 sites in 10 countries.

Additionally, updated results from the single-site study done at UPenn’s Abramson’s Cancer Center provide evidence that after response, CAR T-cell treatment is highly durable. For example, of the 28 patients who received the therapy in this trial after their cancer has relapsed from standard therapy, 43% of the DLBCL patients achieved complete remission along with 71% of the patients with follicular lymphoma, the second-most common form of NHL. Patients who were in remission after 6 months are still in remission after a median follow-up of 28.6 months. A link to the New England Journal of Medicine publication (December 10, 2017) describing the single site trial can be found at the end of this article, of whom the senior author is Carl June, MD, Richard W. Vague Professor in Immunotherapy, Director of the Center for Cellular Immunotherapies, and Director of the Parker Institute for Cancer Immunotherapy at UPenn. The durability of this CAR T-cell treatment makes leaps above the current treatments for when frontline chemotherapy fails and disease relapse occurs.

The major side-effect of concern with CAR T-cell therapy is called cytokine release syndrome (CRS), in which flu-like symptoms such as high fever, muscle pain, nausea occur. Sometimes ICU-level care is needed. In the multi-site study, 58% of the patients experienced CRS, but all cases resolved either with or without additional treatments and there were no treatment-related deaths. CRS was reports in 5 patients from the single site trial as well, which were also all eventually resolved.

UPenn is also involved in studying CAR T-cell therapies beyond CTL019 to treat myeloma, multiple myeloma, and B-cell ALL by using T-cells targeted to NY-ESO-1 (myeloma), CD22 (B-cell ALL), and a particular kind of engineered T-cell called CART-BCMA to target multiple myeloma. In particular, it was announced by UPenn, also on December 11th, that two clinical trials involving BCMA in multiple myeloma are currently ongoing, led by Adam Cohen, MD (Assistant Professor of Hematology and Oncology at Penn and the Director of Myeloma Immunotherapy in Penn’s Abramson Cancer Center). The first involves using CART-BCMA engineered T-cells to target multiple myeloma, which is known to express high levels of B-cell maturation antigen (BCMA). The other trial is examining a chemotherapy drug called MMAF linked to a monoclonal antibody specific to BCMA, resulting in targeted delivery of MMFA to multiple-myeloma cells with high levels of BCMA. The initial results are promising and should lead to more advancements in the treatment of multiple myeloma.

[Press release--Multiple Myeloma] [Press release--Advanced Leukemia] [Press release--Non-Hodgkin Lymphoma] [NEJM article]