New approach could limit toxicity of CAR T therapy in acute myeloid leukemia

May 31, 2018, Perelman School of Medicine at the University of Pennsylvania
Bone marrow aspirate showing acute myeloid leukemia. Several blasts have Auer rods. Credit: Wikipedia

A new approach pioneered at the University of Pennsylvania's Abramson Cancer Center may provide a new path towards treating Acute Myeloid Leukemia (AML) with CAR T cells. To treat AML, investigators have to target a specific protein—CD33—that's also expressed on healthy cells, meaning the therapy cannot attack the cancer without causing other serious damage to the residual normal bone marrow. The new method uses the gene editing tool CRISPR/Cas9 to remove CD33 from healthy blood-forming stem cells, leaving the cancerous cells as the only targets left for the CD33 hunter cells to attack. Penn researchers and their collaborators at the National Institutes of Health published their proof-of-concept findings in Cell today.

AML is the second most common type of leukemia, and the American Cancer Society estimates there will be almost 20,000 new cases in the United States this year. Many of these patients will undergo a bone marrow transplant. To treat a related leukemia called acute lymphoid leukemia (ALL), investigators at Penn previously developed CAR T cell therapy, which involves collecting patients' own immune T , reprogramming them to kill cancer, and then infusing them back into patients' bodies. Currently, both CAR T cell therapys approved for use by the U.S. Food and Drug Administration target cells that express a protein called CD19, for ALL and non-Hodgkin's lymphoma. However, this is not an effective target for AML, since AML does not express CD19. Researchers have therefore been looking for other potential cellular targets.

One promising example is a protein known as CD33, but previous attempts to target CD33 have proven damaging to . While damage to healthy cells could be prevented by making the CART cells short-lasting, this would defeat the purpose of one of CAR T's greatest strengths—their ability to last for years, circulate in the body, and protect the patient from relapse.

"This therapy is meant to be a true living drug, and we know that CAR T cells can live on in patients' bodies for years after infusion, so turning them off would be self-defeating," said the study's co-senior author Saar I. Gill, MD, Ph.D., an assistant professor of Hematology-Oncology at Penn. Cynthia E. Dunbar, MD, a senior investigator at the National Heart, Lung, and Blood Institute, is a co-senior author. The co-first authors are Miriam Yunhee Kim, MD, then a post-doctoral researcher in Gill's lab, and Kyung-Rok Yu Ph.D., a post-doctoral fellow under Dunbar.

"This study represents a significant advance toward effective and safe targeting of leukemia cells using CAR T cells," Dunbar said. "A key to this advance is the use of next-generation gene-editing technology to achieve this type of antigen-specific immunotherapy, even when the target is also present on normal ."

Since the hunter cells are unable to distinguish between normal and malignant cells, the researchers developed an innovative approach to genetically engineer the normal stem cells so they no longer resemble the leukemia. They used the CRISPR/Cas9 gene editing tool to remove CD33 from healthy cells. To their surprise, healthy lacking CD33 functioned normally. This resulted in the CD33 protein now being unique to the , leaving the CAR T cells free to attack.

"None of the existing CAR T approaches target a cancer-specific antigen—other than EGFRvIII in brain cancer—but with this approach, we can create a cancer-specific antigen, which allows us to unleash CAR T cells to their maximal capacity," Gill said.

Gill and his team have already put this concept into practice and have shown it to be effective in mouse and monkey models. They've also demonstrated its effect on human cells in a laboratory setting.

"Think of this as transplant 2.0; the next generation of transplants," Gill said. "It gives you a super powerful anti-leukemia effect thanks to the CAR T cells, but at the same time it has the potential to get rid of the main toxicity."

Their next step is to move this approach into human trials at Penn.

Explore further: New CAR T case study shows promise in acute myeloid leukemia

Related Stories

New CAR T case study shows promise in acute myeloid leukemia

May 9, 2018
Chimeric Antigen Receptor T-cell therapy, also known as CAR T therapy, was named the biggest research breakthrough of 2017 by the American Society of Clinical Oncology. The personal gene therapy utilizes a patient's own immune ...

CRISPR enhances cancer immunotherapy

March 6, 2018
Last year, the Food and Drug Administration approved the first cellular immunotherapies to treat cancer. These therapies involve collecting a patient's own immune cells—called T cells—and supercharging them to home in ...

Bolstering fat cells offers potential new leukemia treatment

October 16, 2017
Killing cancer cells indirectly by powering up fat cells in the bone marrow could help acute myeloid leukemia patients, according to a new study from McMaster University.

As leukemia evolves, stem cells hold keys to newer therapies

August 30, 2016
A recent study by University of Rochester Medical Center researchers proves why leukemia is so difficult to treat and suggests that the current approach to drug development should be adjusted to target a broader range of ...

Using software, researchers predict tumor markers that could be immune targets

December 11, 2017
University of North Carolina Lineberger Comprehensive Cancer Center scientists have developed a software program that can accurately predict which tumor-specific markers will show up on the surface of leukemia cells in patients ...

Fred Hutch researchers engineer complex immunotherapy that may target relapsing leukemia

October 25, 2017
Oct. 25, 2017 - Researchers at Fred Hutchinson Cancer Research Center and the University of Washington have developed a novel way to genetically engineer T cells that may be effective for treating and preventing leukemia ...

Recommended for you

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Researchers create novel combination as potential therapy for high-risk neuroblastoma

June 18, 2018
Researchers at VCU Massey Cancer Center in Richmond, Virginia, have identified a promising target to reverse the development of high-risk neuroblastoma and potentially inform the creation of novel combination therapies for ...

Study suggests well-known growth suppressor actually fuels lethal brain cancers

June 18, 2018
Scientists report finding a potentially promising treatment target for aggressive and deadly high-grade brain cancers like glioblastoma. But they also say the current lack of a drug that hits the molecular target keeps it ...

Standard myelofibrosis drug can awaken 'dormant' lymphoma

June 18, 2018
Most patients with myelofibrosis, a rare chronic disorder of the haematopoietic cells of the bone marrow, benefit from drugs from the JAK2 inhibitor class: symptoms are relieved, survival extended and general quality-of-life ...

Genomics offers new treatment options for infants with range of soft tissue tumors

June 18, 2018
The genetic causes of a group of related infant cancers have been discovered by scientists at the Wellcome Sanger Institute, the University of Wuerzburg and their collaborators. Whole genome sequencing of tumours revealed ...

Breast cancer researcher warns against online genetic tests

June 18, 2018
We have never been so fascinated by the secrets inside our cells.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.