Improving potential of cellular therapies with CAR T therapy

CAR T cells, or engineered immune cells, have demonstrated to the world the potential of customized immunotherapies to treat blood cancers. Researchers have just released highly encouraging preliminary data for CAR T therapy in a small group of lupus patients.

Improving potential of cellular therapies with CAR T therapy
Carl June, MD, and Daniel Baker. Image Credit: Penn Medicine

In a commentary that was published in Cell, Carl June, MD, a pioneer in CAR T therapy at Penn Medicine, and Daniel Baker, a doctoral student in cell and molecular biology at the Perelman School of Medicine at the University of Pennsylvania, describe this development.

We have always known that in principle, CAR T therapies could have broad applications, and it is very encouraging to see early evidence that this promise is now being realized.

Carl June, MD, Richard W. Vague Professor, Immunotherapy, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

One of the immune system’s most potent tools is the T cell. They have the ability to bind to and kill other cells, including virus-infected cells, which they identify as legitimate targets. CAR T cells are T cells that have undergone genetic engineering reprogramming to effectively kill predetermined cell types.

The cells used in CAR T therapies are taken from the blood of the patient, engineered, and multiplied in the lab before being re-infused into the patient as a “living drug.” Kymriah, the first CAR T therapy, was created by June and his Penn Medicine team, and it was approved by the Food & Drug Administration in 2017. In the US, there are currently six CAR T cell therapies that have received FDA approval for treating various cancers.

The therapies have transformed the way that some B cell leukemias, lymphomas, and other blood cancers are treated, putting many patients into long-term remission who would not have otherwise had much hope.

From the beginning of CAR T research, experts thought that T cells could be modified to treat a range of diseases besides B cell cancers. Numerous research groups around the globe, including those at Penn Medicine and biotech spinoffs, are investigating these potential new applications for customized cellular therapy constructs that Penn has developed.

The commentary from June and Baker follows the publication in Nature Medicine of a study by German researchers on the use of CAR T therapy against the autoimmune disease lupus (systemic lupus erythematosus), which is the first significant clinical report of success from these efforts.

Due to the fact that lupus is also driven by B cells and that experimental CAR T therapies for it can use existing anti-B-cell strategies, researchers say lupus is an obvious candidate for CAR T therapy. B cells, which make antibodies for the immune system, develop in lupus patients and attack their own organs and tissues.

The patients in the German study, five young adults, did not experience any benefits from traditional lupus treatments. Nevertheless, after receiving a single, relatively low dose of CAR T therapy that essentially removed their existing B cells, all patients entered remission and were able to stop taking their lupus medicines within three months.

To maintain some antibody immunity, cancer patients subsequently need infusions of purified human antibodies from healthy volunteers. Even more astoundingly, all of the patients maintained their remission throughout the follow-up period of up to a year, and unlike cancer patients, the lupus patients saw a natural replenishment of their B cells, which come from blood stem cells in the bone marrow.

Despite the need for larger studies and longer-term follow-up, Baker and June point out in their commentary that the German study’s findings are highly encouraging and even imply that lupus could end up being a simpler CAR T target than B-cell cancers.

Disease-driving B cells are much less numerous in lupus. Thus, effective CAR T treatment of this autoimmune disease may require a much lower dose that greatly reduces the problem of immunological side-effects.

Daniel Baker, Doctoral Student, Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania

Source:
Journal references:
  1. Baker, D. J., et al. (2022). CAR T therapy extends its reach to autoimmune diseases. Cell. doi.org/10.1016/j.cell.2022.10.026
  2. Mackensen, A., et al. (2022). Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nature Medicine. doi.org/10.1038/s41591-022-02017-5

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