Reengineering CAR T Cells to Optimize Their Powers

Chimeric antigen receptor (CAR) T cells are a patient’s own, harvested and reengineered to attack specific malignant cells. They were initially developed using knowledge gleaned from allogeneic stem cell transplants: that donor mature immune cells can attack healthy cells in the recipient patient.¹

Now, researchers from the UNC Lineberger Comprehensive Cancer Center are set on improving upon these initial gene therapy breakthroughs, balancing the benefits of the therapy with its sometimes serious adverse effects (AEs). Their recent study in Cancer Cell shows how they were able to increase the activity of CAR T cells against tumors or downgrade in the case of debilitating AEs, striving to produce a safer, more predictable therapy.²

AEs of CAR T cells include cytokine release syndrome, low blood pressure, neurologic events (eg, encephalopathy, aphasia, seizures, altered consciousness), neutropenia, and anemia. These can be managed via medication or resolve without treatment.³

“In immunology, it’s always about balance; you don’t want to have too much T-cell activation, and you don’t want T-cell activation to be too low,” stated Peishun Shou, PhD, postdoctoral research associate at UNC Lineberger and the study's co—first author. “We wanted to keep the T-cell activation and tumor killing at a suitable or sustainable level.”

To redirect CAR T-cell activity, they looked at how the CD28 and 4-1BB proteins stimulate CAR T activity in B-cell malignancies, as they are affected by SHP1 phosphatase and LCK kinase, respectively.

For the CAR T cells costimulated by CD28, the authors discovered that if they could pharmacologically increase binding of the SHP1 molecule to the CART T, they could reduce cell activity. This “safety switch” could be used to tone down the CAR T-cell activity in patients experiencing severe AEs.

For the CAR T cells costimulated by 4-1BB, the investigators increased LCK molecule expression, which ramped up their activity. This essentially imparted these CAR T cells with extra tumor-killing power.

“Our mechanistic discoveries have immediate translational implications because kinases and phosphatases can be engineered in CAR-T cells to either enhance or tune down their activation,” the authors noted.

Researchers in the field of immunology hope to build on these findings. Their next steps include investigating how to improve the use of CAR T cells in blood cancers, specifically leukemia, and experimental treatments for solid tumors.

In Other CAR T-Cell News

The next generation of CAR T-cell therapies was front-and-center at the recent 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida. Both abstracts and presentations detailed the expansion of these genetically engineered wunderkinds to improve upon current therapies, simplify their manufacturing, and make them more affordable.

The FDA has so far approved 2 CAR T-cell therapies. Kymriah (tisagenlecleucel, Novartis) is approved to treat adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and young adult patients (aged ≤25 years) with R/R acute lymphoblastic leukemia. Yescarta (axicabtagene ciloleucel, Kite Pharma), meanwhile, has 4 indications if a patient has not responded or relapsed after 2 or more lines of therapy: DLBCL, primary mediastinal BCL, high-grade BCL, and DLBCL from follicular lymphoma.⁴

References

1. Essell JH. The history behind the development of CAR-T cell therapy. Cure^® website. curetoday.com/articles/the-history-behind-the-development-of-car-t-cell-therapy. Published February 8, 2018. Accessed January 28, 2020.

2. Sun C, Shou P, Du H, et al. THEMIS-SHP1 recruitment by 4-1BB tunes LCK-mediated priming of chimeric antigen receptor-redirected T Cells. Cancer Cell. 2020;1-10. doi: 10.1016/j.ccell.2019.12.014.

3. CAR T-cell therapy: risks/benefits Cleveland Clinic website. my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy/risks—benefits. Updated June 27, 2018. Accessed January 28, 2020.

4. FDA-approved CAR T-cell Therapies. UPMC Hillman Cancer Center website. hillman.upmc.com/mario-lemieux-center/treatment/car-t-cell-therapy/fda-approved-therapies. Accessed January 28, 2020.