New Treatment Combination with CTL019 Targets Precursors of Cancerous White Blood Cells

Philadelphia (Press Release) – A multiple myeloma patient whose cancer had stopped responding after nine dif­fer­en­t treat­ment regi­mens ex­peri­enced a com­plete remission after receiving an inves­ti­ga­tional per­son­al­ized cellular ther­apy known as CTL019 developed by a team at the University of Pennsylvania. The inves­ti­ga­tional treat­ment was com­bined with chemo­ther­apy and an au­tol­o­gous stem cell trans­plant – a new strat­egy designed to target and kill the cells that give rise to myeloma cells.

The team’s findings are published in a case report today in the New England Journal of Medicine. Prior to receiving the ther­apy, the patient had already received nine dif­fer­en­t ther­apy regi­mens in the five years since her diag­nosis, in­­clud­ing a pre­vi­ous au­tol­o­gous stem cell trans­plant, which had only controlled her disease for a few months. Her bone marrow was almost entirely filled by can­cer­ous cells when she entered the study. By 130 days after receiving the infusion of engi­neered cells, tests revealed no evi­dence of disease. The patient – who was the first to be treated as part of this trial – remains in remission more than 12 months after receiving this ther­apy.

The new report expands on data that were presented during the American Society of Clinical Oncology meeting in June 2015 about the first five myeloma patients to receive CTL019, which was tested in trials for leukemia beginning in 2010. Now, the Penn researcher team also report updates on the myeloma trial’s over­all progress: Of ten patients who have received the ther­apy to date, six remain pro­gres­sion-free, though two patients have only very recently been treated.

“We couldn’t be more pleased with this patient’s response,” said the study’s co-lead author, Alfred Garfall, MD, an assistant professor of Hematology/Oncology in Penn’s Abramson Cancer Center and Perelman School of Medicine. “We believe her CTL019 cells made the dif­fer­ence, since we would not have ex­pec­ted such a durable remission with a trans­plant alone, con­sidering the very transient response this patient had to her first trans­plant several years ago.”

CTL019 begins with each patient’s own T cells, collected through a procedure similar to dialysis. The cells are then reprogramed to hunt and poten­tially kill cancer cells in the patient’s body. Patients who have en­rolled in trials of this ap­proach for acute lymphoblastic leukemia (ALL), chronic lym­pho­cytic leukemia (CLL), and non-Hodgkin lym­phoma (NHL) typically undergo lymphodepleting chemo­ther­apy before receiving an infusion of their newly engi­neered cells. The modified T cells con­tain a protein known as a chi­meric anti­gen re­cep­tor (CAR), which is designed to target the CD19 protein found on the surface of B cells, in­­clud­ing the can­cer­ous B cells that char­ac­ter­ize several types of leukemia and lym­phoma.

The team designed a dif­fer­en­t ap­proach to study the ther­apy in myeloma, adding in an infusion of the patient’s own stem cells along with their lymphodepleting chemo­ther­apy (melphalan), followed by CTL019 infusion about two weeks later. Although myeloma is, like leukemias and lym­phomas, a cancer involving white blood cells known as lym­pho­cytes, myeloma cells don’t traditionally express CD19 on their surface because they arise from the most mature type of lym­pho­cytes – plasma cells.

“There was some skepticism about whether a CD19-directed ther­apy would work in this disease, since nearly all of these patients’ can­cer­ous plasma cells do not express CD19,” said the study’s senior author, Edward Stadtmauer, MD, chief of Hematologic Malignancies and a professor of Hematology/Oncology in Penn’s Abramson Cancer Center and Perelman School of Medicine. “Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a ther­apy targeted at early precursors of those cells.”

The patient ex­peri­enced trans­plan­ta­tion-related side effects during the time prior to receiving CTL019, in­­clud­ing neu­tro­penia and thrombo­cytopenia, nausea, fever, and an in­fec­tion. After receiving the engi­neered cells, she ex­peri­enced no fevers or other signs of cytokine release syn­drome (CRS), a con­di­tion that has been observed in other patients undergoing CTL019.

Funding for the study was sup­ported in part by Novartis, by grants from the National Institutes of Health (K12CA076931, K08CA166039, and 5R01CA165206) and the Conquer Cancer Foundation.

The University of Pennsylvania has licensed tech­nolo­gies involved in this trial to Novartis. Some of the scientists involved in these trials are inventors of these tech­nolo­gies. As a result of the licensing rela­tion­ship with Novartis, the University of Pennsylvania receives sig­nif­i­cant financial benefit, and these inventers have benefitted financially and/or may benefit financially in the future. Additional disclosure in­­for­ma­tion is avail­able in the paper.

Because CTL019 is an inves­ti­ga­tional ther­apy, the safety and efficacy profile has not yet been estab­lish­ed. Access to inves­ti­ga­tional ther­a­pies is avail­able only through carefully controlled and monitored clin­i­cal trials. These trials are designed to better under­stand the poten­tial benefits and risks of the ther­apy. After CTL019 infusion, cytokine release syn­drome (CRS) may occur when the engi­neered cells become activated and multiply in the patient's body resulting in the release of cytokines. During CRS, patients typically ex­peri­ence varying degrees of flu-like symp­toms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing dif­fi­culties. CRS severity correlates with disease burden. Additionally, CRS also can occur in other non-CAR ther­apy settings in­­clud­ing some mono­clonal anti­bodies.

Source: The University of Pennsylvania.