Mounting Success in Trials of Genetically Engineered T Cells to Treat Leukemias and Lymphomas

Get Permission

David L. Porter, MD

Stephan A. Grupp, MD, PhD

Michael Kalos, PhD

James N. Kochenderfer, MD

Reports have been trickling in from centers conducting research on the use of chimeric antigen receptor–modified T cells (CAR-T) in hematologic cancer, and the news is encouraging. When directed against CD19, such personalized therapeutic T cells are known as CTL019, and small pilot trials of this treatment have shown dramatic improvement in some patients who had been gravely ill.

Investigators from different institutions reported experience to date with CTL019 in patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans. The abstracts summarized here represent studies that are furthest along in the development of CTL019; at least seven other oral presentations at the ASH meeting focused on experience from other institutions.

‘Smart Bomb’ Approach

The promise of the “smart bomb” approach with this immunologic therapy has attracted industry to partner with some investigators and their institutions. For example, CAR-T cells developed at the National Cancer Institute have been licensed to Kite Pharmaceuticals, and CAR-T cells developed at the University of Pennsylvania have been licensed to Novartis. In fact, Novartis is building a manufacturing facility to produce these cells near the University of Pennsylvania campus. Most recently, Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and Seattle Children’s Research Institute have joined forces to launch Juno Therapeutics, a new biotechnology company that will develop CAR-T cells.

Experts predict that CTL019 therapies may become commercially available sometime between 2016 and 2020.

The approach harnesses the power of the immune system by reprogramming a patient’s own T cells to recognize cancer cells for a precision immunologic attack. The patient’s cells are extracted, engineered ex vivo to include CAR, and programmed to target the CD19 antigen present on most leukemic cells. A viral vector is inserted, and then the cells are reinfused into the patient for a single treatment. The viral vector triggers the T cells to expand and proliferate once they are reinfused. The engineering process takes about 10 days.

In several pilot studies, patients have experienced varying degrees of the cytokine release syndrome, which is characterized by high fevers, muscle pain, low blood pressure, and breathing difficulties. The University of Pennsylvania investigators initially showed that the interleukin-6 inhibitor tocilizumab (Actemra) tamps down this response,1 which typically is seen when the engineered T cells are expanding in the body, and several of the groups have reported rapid improvement in the cytokine release syndrome after treating with this drug.

Acute Lymphoblastic Leukemia

Stephan A. Grupp, MD, PhD, Director of Translational Research in the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia and Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, reported on experience with relapsed/refractory ALL in adults and children.2 Twenty-two pediatric patients and five adult patients with relapsed, treatment-resistant ALL have been treated with CTL019 at the University of Pennsylavnia.

Among the children, 19 achieved a complete response, and remission is ongoing in 14, with 5 patients experiencing relapse. The first patient treated with the protocol remains in remission 20 months later. All five of the adults achieved complete remission, the longest of which has been 6 months. One patient subsequently underwent bone marrow transplant and remains in remission. One patient relapsed after 3 months in complete remission, and his disease tested negative for the engineered cell target. The overall complete response rate in this group was 89%.

“Our results serve as another important milestone in demonstrating the potential of this treatment for patients who truly have no other therapeutic options,” Dr. Grupp said.

A separate report from the University of Pennsylvania discussed the quantity, lifespan, and activity of the engineered T cells once they were reinfused into the pediatric and adult patients with ALL (described above) and adults with advanced relapsed/refractory CLL.3 Testing showed that patients with the greatest in vivo expansion of CTL019 cells (to more than 5% of all CD3-positive cells) were the most likely to achieve complete remission. Those with less robust but still detectable cell expansion were partial responders, while those with no or minimal detectable T-cell expansion were nonresponders. The CTL019 cells that were detected persisted for many months after infusion and continued to function as anticancer T cells.

“These new and expanded data provide significant proof that T cells engineered to express cancer-targeting CARs not only work, but work dramatically and in a sustained manner in patients with relapsed/treatment resistant leukemia. [The results] further demonstrate the potential of this approach to help these patients achieve complete remission,” said study author Michael Kalos, PhD, Director, Translational and Correlative Studies Laboratory, Stellar-Chance Laboratories, and Adjunct Associate Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania.

“Further, … we can potentially measure and track these engineered cells as a way to monitor treatment, an exciting finding considering that this treatment is often the last hope for these patients,” he added.

Chronic Lymphocytic Leukemia

David L. Porter, MD, Director of Blood and Marrow Transplantation at the University of Pennsylvania’s Abramson Cancer Center, reported on experience in the treatment of 32 adults with CLL. Fifteen patients (47%) responded to therapy (7 complete responses and 15 partial responses). The complete remissions are ongoing, he noted.

The 32 CLL patients included 14 who were in the pilot trial and the first 18 in a phase II dose-optimization trial.4,5

“We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells,” Dr. Porter said. “We’ve now seen remissions lasting for more than 3 years, and there are clues that the T cells continue to kill the leukemia cells in the body for months after treatment. Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow and their lymph nodes continued to shrink over time. In some cases, we have seen partial responses convert to complete remissions over several months.”

First Report in B-Cell Lymphoma

James N. Kochenderfer, MD, an investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute, Bethesda, Maryland, described successful treatment with anti-CD19 CAR-T cells in a total of 15 patients with chemorefractory B-cell lymphomas: 9 had aggressive large B-cell lymphomas, and 6 had a variety of indolent B-cell lymphomas. Patient ages ranged from 30 to 68 years.6

“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that—until this point—were virtually untreatable and have a very poor prognosis. The novel finding is that anti-CD19 CAR-T cells can eradicate a solid tumor mass,” Dr. Kochenderfer said.

Patients underwent a conditioning regimen with cyclophosphamide and fludarabine prior to receiving a single infusion of their own genetically modified T cells. This conditioning regimen was used because prior chemotherapy has been shown to enhance the activity of anti-CD19 CAR-T cells in patients.

Seven patients achieved a complete response, five achieved a partial response, and one patient had stable disease. One patient died of cardiac arrhythmias, and a second patient was lost to follow-up. Acute toxicities included fever, low blood pressure, focal neurologic deficits, and delirium. These toxicities resolved in less than 3 weeks.

“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options,” Dr. Kochenderfer said. “This approach offers an option for patients with chemotherapy-refractory large B-cell lymphomas who are generally not thought to be good candidates for hematopoietic stem cell transplantation.”

In the protocol used by Dr. Kochenderfer and co-investigators, the CAR is encoded by a gamma retrovirus and incorporates regions of an anti-CD19 antibody, part of CD28, and part of CD3-zeta. The anti-CD19 CAR-T cell protocols are evolving and still in early stages, he noted.

“We will continue our research to further improve the protocol and evaluate its value in additional patients with treatment-resistant disease,” he said. ■

Disclosure: The NCI trial was supported in part by Kite Pharma. Dr. Kochenderfer has no personal financial ties and has received no payments from Kite Pharma. Dr. Porter reported research funding and intellectual property/royalties in association with Novartis, as well as spouse employment with Genentech. Dr. Kalos reported patents and royalties in association with Novartis and is a member of the scientific advisory board for Adaptive Biotechnologies. Dr. Grupp receives research funding from Novartis.


1. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013.

2. Grupp S, Frey NV, Aplenc R, et al: T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce significant in vivo proliferation, complete responses, and long-term persistence without GVHD in children and adults with relapsed, refractory ALL. ASH Annual Meeting. Abstract 168. Presented December 8, 2013.

3. Kalos M, Nazimuddin F, Finklestein JM, et al: Long-term functional persistence, B cell aplasia, and anti-leukemia efficacy in refractory B cell malignancies following T cell immunotherapy using CAR-redirected T cells targeting CD19. ASH Annual Meeting. Abstract 163. Presented December 8, 2013.

4. Porter D: Randomized phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. ASH Annual Meeting. Abstract 873. Presented December 10, 2013.

5. Porter D, Kalos M, Frey N, et al: Chimeric antigen receptor modified T cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL. ASH Annual Meeting. Abstract 4162. Presented December 9, 2013.

6. Kochenderfer J, Dudley ME, Kassim SH, et al: Effective treatment of chemotherapy-refractory diffuse large B-cell lymphoma with autologous T cells genetically-engineered to express an anti-CD19 chimeric antigen receptor. ASH Annual Meeting. Abstract 168. Presented December 8, 2013.

Related Articles

Expert Point of View: Prashant Kapoor, MD

At the recent American Society of Hematology Annual Meeting, Prashant Kapoor, MD, Assistant Professor of Hematology at Mayo Clinic, Rochester, Minnesota, agreed that CTL019 is a promising, exciting, and novel approach to treating patients with advanced B-cell hematologic malignancies.