New CAR T-cell therapy for relapsed leukemia patients
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New CAR T-cell therapy for relapsed leukemia patients

Team Representatives:
Crystal Mackall, MD
Professor of Pediatrics (Hematology/Oncology) and of Medicine, Stanford University

Nirali N. Shah, MD, MHSc
Associate Research Physician, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute

Terry J. Fry, MD
Principal Investigator, Special Volunteer, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute

Media Contacts: 
National Cancer Institute Press Officers
Phone: 240-760-6600

Kris Newby
Phone: 650-867-8862

Summary of findings in layman's terms: 

A significant percentage of children and young adults with treatment-resistant B-cell leukemia achieved remission through a new CAR T-cell gene therapy that destroys cancer cells with the CD22 molecule on its surface. 

T-cells are immune system cells that patrol the body for harmful microbes and cancer cells. In most cases, cancers evade detection by the T-cells. CAR therapy works by genetically modifying a person’s own T-cells to express a synthetic receptor that allows cancer cell recognition. When a CAR expressing T-cell detects a cancer cell, the T-cells are triggered to kill the invader. 

CAR T-cells targeting CD19 have demonstrated impressive activity and are now approved by the Food and Drug Administration. However, at least 30% of patients will relapse following CAR T cell therapy due to selection of leukemic cells that lack CD19. In this trial, researchers genetically modified patients T-cells to express a CAR targeting a surface antigen called CD22. These engineered T-cells were then released back into a patient’s body to kill cancer cells previously unrecognized by the immune system.

The CD22-CAR T-cells induced remissions in patients regardless of CD19 expression. Therefore, the new CD22 approach provides a way to salvage patients whose cancers no longer respond to the original CD19 CAR therapy. It also opens the door to combination treatments that may increase the odds of shutting down the cancer. 

Specific biological innovation of study: 

This study, published in Nature Medicine, tested a novel CAR that was developed in the Mackall laboratory at the National Cancer Institute (NCI) in a first-in-human, first-in-child study conducted by Drs. Fry, Shah, and colleagues in the NCI Center for Cancer Research’s Pediatric Oncology Branch at the NIH Clinical Center. It provided the first evidence that CAR T cells targeting an antigen other than CD19 can also mediate impressive antitumor effects. The study is the first to show that patients rendered into remission with CD19-directed immunotherapy, who then relapsed, could be rescued by a different T-cell immunotherapy, providing evidence for salvage immunotherapy. The study identified that the most common mechanism of relapse following CD22-CAR therapy was selection of antigen-low variants, that were also able to evade detection by the CAR receptor. 

Finally, this study also opens the door to the use of multiple CAR targets to fight treatment-resistance leukemia. Investigators demonstrated in the manuscript that incorporating both the CD19-CAR and CD22-CAR into one receptor can prevent selection of CD19-negative variants. 

Potential impact on human care and/or how the findings contributed to an improved understanding:

B-cell acute lymphoblastic leukemia is the most common cancer in children, and it is usually successfully treated with chemotherapy. However, patients who don’t respond to initial treatment, or whose cancer recurs after a remission, often have a much poorer prognosis. This approach offers hope to these treatment-resistant patients.

In this phase-1 study, fifteen of 21 patients who had previously relapsed or failed to respond to CD19 CAR T-cell treatment went into remission. 

By developing a CAR T-cell therapy that targets a second target on malignant cells, it may help leukemia patients whose cancer cells lack the C19 molecule or lose it.

At the lowest dose level, one in six patients achieved complete remission after treatment with the anti-CD22 CAR T cells. However, when the researchers escalated the dose to the next level in the study, 11 of 15 patients, or 73 percent, entered remission. The remissions lasted a median of six months; three patients remain in complete remission at six, nine and 21 months after the therapy. These are promising results for an early trial involving very ill leukemia patients.

The study suggests that combination immunotherapy with both CD19 and CD22 may produce longer-lasting remissions. 

Journal citation: 

CD22-targeted CAR T cells induce remission in B- ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, Shalabi H, Fountaine TJ, Shern JF, Majzner RG, Stroncek DF, Sabatino M, Feng Y, Dimitrov DS, Zhang L, Nguyen S, Qin H, Dropulic B, Lee DW, Mackall CL.

Nat Med. 2017 Nov 20. doi: 10.1038/nm.4441.[Epub ahead of print] PMID: 29155426