Skip to Main Content

Advertisement intended for health care professionals

Skip Nav Destination

CAR T Therapies: Engineering a Breakthrough in Lymphoma and Leukemia Treatment

December 30, 2021

Novel therapies that harness the body's own immune cells to attack cancer cells took center stage at this year's annual meeting. Across a variety of settings, genetically engineered chimeric antigen receptor T (CAR T) cells demonstrated safe and durable responses in patients with relapsed and treatment-resistant blood cancers.

"CARs are living drugs," Carl H. June, MD, from the Abramson Cancer Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia, said during the standing-room-only "Special Scientific Symposium on Chimeric Antigen Receptor T-Cell Therapy." Dr. June and other speakers discussed the mounting enthusiasm for these "natural born killers," as well as some of the novel settings in which CAR T therapy is being investigated.

"What we have is an ability to target cancer cells based on an antigen that is expressed on the surface of B cells," Stephan A. Grupp, MD, PhD, director of translational research for the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia, said during a press briefing discussing novel immunotherapeutic approaches.

"In theory, anything that you can build a monoclonal antibody to, you might be able to target with a CAR." Two studies presented at this year's annual meeting highlight CAR T therapies' promise in two difficult to-treat disease settings: pediatric acute lymphocytic leukemia (ALL) and treatment-resistant, relapsed Hodgkin lymphoma (HL).

Can CAR T Replace Transplant in Pediatric ALL?
While that is his "fondest hope" for this promising new treatment approach, we are not there quite yet, Dr. Grupp said during a discussion of the results from his research group's study of CD19-targeting CAR T in pediatric patients with acute lymphocytic leukemia (ALL). However, long-term disease control may be a possibility.

In their long-term follow-up of CAR T-cell therapy in 39 children and young adults with relapsed, treatment-resistant ALL, Dr. Grupp and colleagues reported that 36 patients (92%) achieved a complete response after being treated with CLT019 – the T-cell therapy tested in this trial.

In July 2014, CTL019 was awarded Breakthrough Therapy designation from the Food and Drug Administration in both pediatric and adult ALL.

Importantly, CTL019 can persist for more than two years – leading to durable remission in these study patients, Dr. Grupp added. Six months after treatment, 70 percent of children enrolled in the study remained cancer-free, and 75 percent have survived. Only three of the 39 patients eventually underwent stem cell transplantation.

Notably, the response induced by CAR T therapy occurred independently of disease burden, except in the case of patients with high disease burden, such as the highly-treatable cytokine-release syndrome. Several of the study patients experienced other toxicities (including encephalopathy and B-cell aplasia) which were eventually resolved without incident or long-term complications, Dr. Grupp explained.

"With this longer follow up, we now have children who remain in remission a year or more after treatment solely because of this T-cell therapy," said Dr. Grupp. For the first time, "we are beginning to see the picture of longer-term persistence and longer-term disease control in ALL."

Clearly, this individualized approach demonstrated a benefit for the 39 patients in this study, but can the treatment approach – harvesting and engineering T cells for every individual – feasibly be implemented on a larger scale? According to Dr. Grupp, the next step is to conduct a phase 2, multicenter trial to assess the safety, efficacy, and feasibility of this treatment in multiple centers across the United States – with the ultimate goal of evaluating its long-term potential to become a replacement for stem cell transplant in this setting.

Targeting CD123: New Hope for Relapsed/Refractory HL
For the 10 to 15 percent of HL patients who relapse or are refractory to first-line therapy, CART123 approaches may improve their typically poor prognosis, according to mice model data presented by Marco Ruella, MD.

Dr. Ruella, of the Abramson Family Research Cancer Institute at the University of Pennsylvania, and others previously demonstrated the efficacy of CD123-targeting CART123 in treating refractory B-cell malignancies. With their latest research, the investigators attempted to translate these findings to patients with refractory HL, using a combined approach of CART123 and rescue autologous bone marrow transplantation.

In a group of 10 mouse models of HL, Dr. Ruella and colleagues searched for a cell membrane antigen associated with HL that could be targeted by CAR T cells – ideally one expressed on neoplastic cells and infiltrating immune cells to provide robust stimulation of the CAR T cells. This target was found in CD123, the alpha chain of the receptor for interleukin-3, an important cytokine that has been shown to promote HL growth. Immunohistochemistry revealed that CD123 was expressed in five out of 10 patients' HRS cells.

After defining the role of IL-3 signaling in HL in in vitro models of the disease, Dr. Ruella and investigators confirmed these results in in vivo models, where, approximately six weeks after injection, mice were treated with 1.5 million CART123 cells or control T cells. "CART123 induced complete and durable eradication of disseminated tumor within 14 days, leading to 100 percent relapse-free and 100 percent overall survival at six months," the investigators reported. Tumor elimination was also associated with extensive CAR T-cell expansion.

"We developed anti-CD123 chimeric antigen receptor T cells and demonstrated that they are highly effective in a preclinical in vivo model of Hodgkin lymphoma," Dr. Ruella told ASH Clinical News. "Since neoplastic cells in Hodgkin lymphoma comprise only 1 to 2 percent of the tumor mass, targeting both the tumor and microenvironment can be particularly important for the long-term eradication of the disease." So, given the promising safety and durable efficacy data of CAR T in these difficult-to-treat diseases, where else will these CARs take us? "We're hoping for a fleet of CARs," Dr. June predicted.


References

  • Ruella M, Kenderian SS, Shestova O, et al. Novel Chimeric Antigen Receptor T Cells for the Treatment of Hodgkin Lymphoma. Abstract #806. Presented at the 2014 ASH Annual Meeting. December 9, 2014.
  • Grupp SA, Maude SL, Shaw P, et al. T Cells with a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Have Long Term Persistence and Induce Durable Remissions in Children with Relapsed, Refractory ALL. Abstract #380. Presented at the 2014 ASH Annual Meeting. December 8, 2014.

Advertisement intended for health care professionals

Connect with us:

CURRENT ISSUE
November 2024

Advertisement intended for health care professionals

Close Modal

or Create an Account

Close Modal
Close Modal

Advertisement intended for health care professionals