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Memory-Related Genes May Overcome Resistance to CAR T-Cell Therapy in CLL

Jason Harris
Published: Thursday, May 03, 2018

J. Joseph Melenhorst, PhD
J. Joseph Melenhorst, PhD
Results from a recent study may show why some patients with chronic lymphocytic leukemia (CLL) are resistant to tisagenlecleucel (Kymriah), while potentially offering a pathway to enhance patient response.

The findings from the University of Pennsylvania may also give physicians a way to identify patients with CLL who are most likely to respond to tisagenlecleucel. While the chimeric antigen receptor (CAR) T-cell immunotherapy has been shown to induce a complete response (CR) rate of ≥80% in patients with B-cell acute lymphoblastic leukemia (ALL), the CR rate is 26% for patients with CLL.

The study, led by senior author J. Joseph Melenhorst, PhD, and first author Joseph A. Fraietta, PhD, both faculty at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, at the Center for Cellular Immunotherapies, demonstrated that patients with healthier, “early memory” cytotoxic T cells were far more likely to have a complete or partial response to treatment. In a validation study, this early memory T cell signature predicted patients who would experience CR with 100% accuracy.

The investigators also found a correlation between high levels of the STAT-3 signaling pathway and a positive response to therapy. Previous study results have shown that the pathway was associated with T-cell persistence.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Fraietta said in a statement. “The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

The Penn team sought to identify the reasons why some patients with CLL have strong responses to CAR T cells while others do not respond at all.

As in previous findings, age, tumor burden, and prior therapies were not predictors for response. Investigators could not identify any patient- or disease-specific predictors.

The research team found that patients who had a CR or partial response with transformed disease (PR/TD) had a “dramatic” expansion of CAR T cells concurrent with B cell aplasia within 2 weeks of infusion. Nonresponders had little or no T-cell proliferation and displayed minimal B cell aplasia.

Detectable CTL019 cells persisted in patients still in CR after 5 years of follow-up.

“It appears that all effective CD19 CAR T-cells, regardless of costimulatory domain, specific T-cell subset enriched for, or disease type treated require in vivo cell expansion and persistence to be effective,” investigators wrote.

After comparing the gene expression profiles and phenotypes of T cells in patients with CR, PR, or no response, the investigators concluded that defining features in the infusion product–early memory and non-exhaustion signatures in CR patients and apoptosis and exhaustion in nonresponding CAR T cell patients–also defined premanufacturing T cells.

Furthermore, the enhanced glycolysis signature in manufactured T cells from nonresponding patients and STAT3 signature in CR patient CAR T cells proved to be an effective way to enrich for the most potent leukemia killers, according to Melenhorst.

“Pre-existing T cell qualities have previously been associated with poor clinical response to cancer therapy, as well as differentiation in the T cells,” Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Investigators conducted a validation study to evaluate the biomarker findings. The early memory T cells from 8 patients were screened before and after CAR T-cell therapy, and accurately predicted the complete responders with 100% sensitivity and specificity.

Investigators believe these results could eventually lead to enhancing a patient’s immune cells with the fast-expanding CD27+CD45RO- CD8+ T cells prior to CAR T-cell therapy.

“What we've seen in these nonresponders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations," Melenhorst said in a release. “But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The FDA approved tisagenlecleucel for pediatric B-cell precursor ALL in August 2017, making it the first approved CAR T-cell therapy in the United States. The agency recently approved a new indication for patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.
Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia [published online April 30, 2018]. Nat Med. doi:10.1038/s41591-018-0010-1.




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