Chimeric antigen receptor (CAR) T-cell therapy has been hailed as one of the great advances in oncology care, but not all patients will respond.
This is particularly the case with relapsed/refractory chronic lymphocytic leukemia (CLL), where durable antitumor complete responses have been observed in only 26% of patients, in contrast to the greater than 90% rate of complete remission that has been observed in acute lymphoblastic leukemia (ALL).
Now researchers may have figured out an important clue as to why only some patients with CLL respond.
Tumor burden, disease characteristics, or features specific to the patient are not sufficient in and of themselves to distinguish clinical outcomes and predict response, they point out. Instead, it seems that “intrinsic T-cell fitness” plays an important role in mediating long-term complete remissions. The finding could have a dramatic effect on patient selection, as well as allow for immune modification that will improve the efficacy of this treatment, the researchers suggest.
The findings were published April 30 in Nature Medicine.
Patients with CLL who had healthier, “early memory” cytotoxic T cells, marked by the expression of CD8 and CD27, as well as the absence of CD45RO, were far more likely to achieve a complete or partial response to treatment.
“Our biomarker, which is defined as CD27-positive, CD45RO-negative CD8+ T cells in pre-manufactured T cells, may help in patient selection,” said senior study author, J. Joseph Melenhorst, Ph.D., director, product development and correlative sciences, at the University of Pennsylvania, Philadelphia. “Patients with 28.6% of the CD8+T cells expressing this phenotype were more likely to respond to CD19-redirected T-cell therapy than patients with a lower frequency of this population.”
Melenhorst noted that this could be used as a selection tool to identify patients who are most likely to benefit from this therapy. “We have other cell therapies in development and such biomarker-negative patients could consider that as an alternative,” he told Medscape Medical News.
This biomarker panel has been tested many times in CLL and it reproduces really well, Melenhorst explained. “But how this would perform on other trials is currently unclear. What is also unclear is whether this same biomarker profile applies to other cancers, which is what we are actively investigating.”
Another question is whether immunologic health can be improved in nonresponding patients. “What we did show in our paper is that we can make the T cells do a better job via pharmacological or genetic manipulation,” he said. “To rescue the truly failed T-cell population in nonresponding patients, we would have to be able to alter the ground state of the T cells to have a meaningful impact, but we have yet to achieve that.”
Study Details
The study included 41 patients with advanced, heavily pretreated and high-risk CLL who had received at least one dose of CD19-directed CAR T cells.
The researchers performed genomic, phenotypic, and functional evaluations in order to identify determinants of response, and results from transcriptomic profiling showed that CAR T cells from patients who had achieved a complete response were enriched in memory-related genes, including IL-6/STAT3signatures. Conversely, T cells from nonresponding patients upregulated programs involved in effector differentiation, glycolysis, exhaustion, and apoptosis.
Patients with a sustained remission had an elevated frequency of CD27+CD45RO– CD8+ T cells before CAR T-cell generation, with their lymphocytes possessing “memory-like” characteristics. Elevated levels of the IL-6/STAT3 signaling pathway, which had been shown to enable T-cell persistence in previous research, in early T cells correlated with the clinical responses in patients after receipt of CAR T-cell therapy.
To validate their findings, the researchers screened eight patients with CLL for the early memory T cells before and after CAR T-cell therapy. Complete responders were identified with 100% specificity and sensitivity.
“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,” said first author, Joseph A. Fraietta, PhD, also from the University of Pennsylvania, in a statement. “The ability to select patients most likely to respond would have a 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.”
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