Experts Discuss Manipulation of T Cells for Therapy in Hematologic Malignancies

Andre Goy, MD, MS

While novel targeted therapies represent an active research interest for the treatment of various hematologic malignancies, finding new ways of manipulating the body’s own defenses to better combat these diseases is yielding some interesting results and could represent a very promising new field of care for patients dealing with these disorders.

Hematologists from across the country discussed some of this emerging research at the program Cell Therapy and Interventional Immunology: Current Developments and Implications, held June 7 at the John Theurer Cancer Center (JTCC) at Hackensack University Medical Center in New Jersey.

“We have been attempting to harness the immune system to fight cancer cells for more than 100 years, and while there has been some success, it hasn’t really translated into a long-lasting benefit,” said Andre Goy, MD, MS, chairman and director and chief of the Division of Lymphoma at JTCC. “Over the last few years, there has been a lot of great development in immunology and a better understanding of it, especially when it comes to trying to unleash T cells to promote their antitumor effects.”

For example, allogeneic hematopoetic cell transplantation (HCT) has been used for years in patients with various hematologic malignancies. One new strategy to improve outcomes and reduce graft-versus-host disease is to combine T cells with rapamycin to form T-rapa cells. Rapamycin is used to block white blood cells from rejecting a transplant and also inhibits the mTOR enzyme, which is needed for tumors to grow and proliferate.

“We’re starving the cells ex vivo, but during that starvation, we’re giving them other signals to keep growing, and cells can survive that under the right conditions, and when they do survive that, they emerge as a more healthy cell,” said Daniel H. Fowler, MD, head of the Cytokine Biology Section and senior investigator at the Center for Cancer Research of the National Cancer Institute in Bethesda, Maryland.

Results of a clinical trial involving 42 patients with high-risk lymphoma who were treated with these T-rapa cells were presented in December at the 54th Annual American Society of Hematology Meeting in Atlanta, Georgia. The study found that the overall median survival probability at 24 months after HCT was 85.7% for patients with chemotherapy-sensitive disease, compared with 39.1% for patients with chemotherapy-refractory disease (P = .0008), suggesting that low-intensity conditioning with T-rapa cells is safe and effective in chemotherapy-sensitive patients.¹

The study of cell therapy could also help patients with rare hematologic disorders with classically poor prognoses, as is the case with Epstein Barr virus (EBV)-positive lymphoma. Researchers have developed a methodology to manipulate T cells from heavily pretreated patients with EBV+ Hodgkin and non-Hodgkin lymphoma so that those T cells target the LMP1 and LMP2 proteins expressed on tumor cells.

“We’ve treated 21 patients with active disease, and with T-cell therapy alone, no chemotherapy, no pretreatment, we’ve seen clinical responses in 13 of the patients, which translates into a progression-free survival rate at 2 years of 50%,” said Catherine Bollard, MBChB, MD, professor, Center for Cell and Gene Therapy at Baylor College of Medicine in Houston, Texas. “This is excellent when you consider historically that sort of patient population would probably have a 10% to 20% progression-free survival rate at that time.”

Bollard also said that 29 patients have been treated in the adjuvant setting either after autologous bone marrow transplant or chemotherapy with this method, and so far, only one patient has relapsed. The 3-year progression-free survival rate is 80%, and Bollard explained that these patients are not dying of lymphoma but rather of causes related to prior treatment with chemotherapy and radiation.

“It highlights to me the importance of really developing these targeted therapies to be used early in the disease treatment process and not leave it too late after the patients have already failed multiple rounds of other therapies that may ultimately result in devastating complications later on,” Bollard said.

Another new development in immunology is the development of tumor-targeted chimeric antigen receptor (CAR) technology. T cells are capable of killing tumor cells, but first they need to be able to recognize the tumor cells as “foreign” and not originating from the host. With a CAR, T cells are taken from the host and the CAR is used to introduce a virus into the T cells. The T cells then express a receptor that allows them to bind to tumor cells once they have been reinserted into the host and effectively kill them off.

Initially, this technology was tested in low-grade B-cell malignancies, but now it’s being utilized in patients with adult B-cell acute lymphocytic leukemia (ALL), a disease with a much worse prognosis. Many patients receive salvage therapy after relapsing on initial treatment, but many of those patients never again achieve remission. A small trial was conducted in these patients to determine whether CAR technology is effective.

“In our trial, we found that all of the patients treated initially—five out of five—tolerated the therapy well, but more significantly, all went into what we call a minimal, residual, disease-negative, complete remission, which is to say that even by highly sensitive detection methods, we could no longer find the B-cell ALL tumor cells,” said Renier Brentjens, MD, a medical oncologist in the Leukemia Service at Memorial Sloan-Kettering Cancer Center in New York City. “Therefore, these patients were ideally or optimally primed for subsequent bone marrow transplantation and had the greatest chance of being long-term survivors.”

The speakers at the meeting discussed plans in which these technologies and new methods of harnessing T cells to combat tumor cells would be implemented in larger clinical trials.

“This is very promising, and we all believe it will translate into enormous clinical benefits, potentially after chemotherapy in high-risk patients that could relapse,” Goy said.

1. Halverson D, Mossoba ME, Steinberg SM, et al. Preemptive T-rapa cell DLI for therapy of high-risk lymphoma after low-intensity allogeneic HCT. Presented at: 54th Annual Meeting of the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Abstract 471.