A recent independent publication cites using HemaCare leukopaks for their evaluation of a CAR T cell therapy’s antitumor potency.
As the CAR T cell therapy field continues to grow, developers seek to refine techniques that will improve both the safety and efficacy of this promising cancer immunotherapy strategy. Scientists at Juno Therapeutics (Celgene) have been working to improve the potency of a CD19-targeted CAR T therapeutic currently in phase 1 and 2 clinical trials.
Kymriah® and Yescarta®, the first CAR T cell therapies to be approved by the FDA, each target CD19, a protein found on the surface of B cells. While both therapies are a formidable weapon against B-cell malignancies, they also have serious limitations. Patients can suffer from high-risk side effects, which in turn means that treatment is restricted to only those patients who have failed to respond to one or more traditional treatments. There is also some risk of relapse; in some patients, the response to CAR T cell treatment is not complete.
The authors hypothesized that an experimental CAR T cell therapy known as Lisocabtagene maraleucel (liso-cel), might be more effective as part of a combination drug treatment. To test this hypothesis, they decided to evaluate the effect of liso-cel CAR T cells in combination with the FDA-approved drugs ibrutinib and acalabrutinib. Both approved drugs help reduce the tumor burden in leukemia and lymphoma patients by blocking abnormal B cell formation.
First, the group set out to examine the effects of the various drug combinations in vitro, to get an idea of their interaction with the CAR T cells in a simple cell culture system. T cells used for this study were isolated from healthy donor leukopaks sourced from HemaCare. Cellular starting material quality directly impacts end product quality, so it is easy to understand why the authors would want to source their materials from the same company that provided materials for both Kymriah® and Yescarta®.
In an elegant series of experiments, the authors showed that combination treatment with either ibrutinib or acalabrutinib improved CAR T cell effector function. Long-term exposure to either drug over a period of 6 days significantly increased CAR T cell expansion, without affecting T cell viability or the ratio of major T cell subtypes. Furthermore, long-term treatment with ibrutinib (18 days) resulted in greater differentiation of CAR T cells into a Memory-like T cell phenotype, increasing the chances of long-term functionality.
The authors continued their work in an in-vivo model, using mice implanted with human CD19-expressing tumor cells. The researchers were able to demonstrate that when tumor-bearing mice were treated with liso-cel CAR T cells in the presence of either ibrutinib or acalabrutinib, CART T cells persisted longer than usual, resulting in increased tumor clearance and survival rates.
This work gives the authors hope that second-generation CAR T cell therapies, used in combination with the more traditional drug treatments studied here, will have longer persistence and greater expansion potential in the patient’s body, leading to better outcomes.
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- Qin J.S., et al. Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination with Ibrutinib or Acalabrutinib. J Immunotherapy. 43:107–120. May 2020.