Investigational compound shows ‘very dramatic’ capability to enhance CAR T-cell efficacy
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Researchers have developed a genetically modified form of the immune-stimulating protein interleukin-7 that significantly enhanced chimeric antigen receptor T-cell therapy activity in preclinical testing.
The addition of the long-acting form of recombinant human interleukin (IL)-7 fused with hybrid Fc (rhIL-7-hyFc) to CAR T cells resulted in survival times nearly six times longer than those seen in mice that received CAR T cells alone, study results published in Nature Communications showed.
Investigators described the novel compound — which recently received FDA’s orphan drug designation for the treatment of glioblastoma multiforme — as a “tunable” adjuvant therapy to improve CAR T-cell activity.
“’Tunable’ in this respect refers to both dose-related and temporally related changes in the administrative strategy, and there are many ways in which we can consider this a modifiable approach,” John F. DiPersio, MD, PhD, Virginia E. and Sam J. Golman professor in medicine, director of Center for Gene and Cellular Immunotherapy, and deputy director of Alvin J. Siteman Cancer Center at Washington University School of Medicine in St. Louis, told Healio.
Altering the dose of rhIL-7-hyFc or continued dosing could achieve CAR T-cell persistence over a longer period, whereas higher doses of rhIL-7-hyFc provided near the time of CAR-T infusion could promote more rapid expansion of CAR T cells, he added.
“All of these outcomes are theoretically possible based on our preclinical research but still need to be evaluated in humans to confirm,” he said.
DiPersio spoke with Healio about the preclinical testing results, the compound’s promise to enhance CAR T-cell performance and the ongoing effort to translate what his group has learned into clinical testing for humans.
Healio: Can you explain the rationale for using a genetically modified form of IL-7 to improve CAR-T performance?
DiPersio: Our research used a variant of IL-7 known as rhIL-7-hyFc (efineptakin alfa, NeoImmuneTech). It is a genetically altered version of IL-7 that is modified to increase biological activity for the ligand itself and the immunoglobulin fragment crystallizable region. These fusions result not only in a larger molecule, but a more active version with an increased half-life of approximately a few weeks in vivo. By comparison, the recombinant version of IL-7 that has been manufactured by several companies over the years has a very short half-life of only a few hours.
Healio: What does a longer half-life for rhIL-7-hyFc mean for CAR T-cell functionality when administered as adjuvant therapy?
DiPersio: Our study showed three impacts on CAR T cells. First, rhIL-7-hyFc dramatically enhanced CAR T-cell expansion and persistence in preclinical mouse models. Second, it increased the number of effector memory CAR T cells. Third, it dramatically enhanced the antitumor efficacy of CAR T cells, whether they were directed against lymphoid targets — such as CD19 — or a myeloid target, including CD33.
Healio: Would the application of rhIL-7-hyFc as part of the CAR-T regimen be limited to CD19-positive lymphoma or CD33-positive leukemia used in your preclinical models?
DiPersio: Because the IL-7 receptor is expressed on all T cells — and on some B cells, as well — our approach would be applicable, in theory, to other CAR-Ts directed toward different targets. IL-7 also is expressed on [invariant natural killer)] T cells and at a lower level on NK cells, so rhIL-7-hyFc could have applications for expanding these cell types, as well. Although we did not test this in our research, because the IL-7 receptor is expressed on T cells, rhIL-7-hyFc could help enhance the expansion and antitumor efficacy of T-cell receptor (TCR)-modified cell therapies.
Healio: Has your research been translated into clinical testing in humans?
DiPersio: Testing of this compound is being done as part of a very early phase 1 study of patients with CD19-positive diffuse large B-cell lymphoma who are receiving tisagenlecleucel (Kymriah, Novartis). The trial is specifically designed to examine treatment-related toxicity and feasibility. A primary focus is on dose-escalation of the drug because the FDA realized that if rhIL-7-hyFc enhances CAR T-cell expansion in humans — as it did in immunodeficient mice — there would be potential benefits for patients, but also potential treatment-related toxicities, such as worsening cytokine release syndrome. Therefore, the FDA has mandated that we test this drug at a time well after CAR T-cell infusion to reduce the risk for significant treatment-related toxicity.
For example, our first study will administer rhIL-7-hyFc on day 21 after CAR-T infusion. This is a time in the CAR-T process when cells have stopped expanding and have significantly contracted. We hope in the future to be able to move the dose of rhIL-7-hyFc closer to the CAR T-cell infusion. By comparison, in our preclinical study, we administered rhIL-7-hyFc on day 1 after CAR T-cell infusion in immunodeficient mice.
Healio: What has clinical testing shown thus far regarding treatment-related toxicity for rhIL-7-hyFc?
DiPersio: So far, we have only treated a handful of patients — approximately five — but there has not been any CRS-related toxicity. However, we have seen the lymphocytes expand after the dose of rhIL-7-hyFc on day 21 after CAR-T infusion.
Healio: How confident are you that this approach can produce additional benefits for patients receiving CAR-T?
DiPersio: That's hard to determine at this point given the difference that some investigational agents show between preclinical models and human testing. The results thus far have been very dramatic in immunodeficient and immunocompetent mouse models but, because the FDA has mandated a large gap between CAR-T infusion and administration of rhIL-7-hyFc, it is hard to predict what type of an impact it will have on treatment efficacy. I do believe that the current trial will give us a good idea about any unexpected treatment-related toxicities.
Going forward, however, I do expect the behavior of CAR T cells to be relatively similar in human testing to what we saw in our preclinical mouse models. I hope — based on the preclinical models — that providing rhIL-7-hyFc as an adjuvant therapy to CAR T cells will provide clinical benefits to patients.
For more information:
John F. DiPersio, MD, PhD, can be reached at Washington University, Division of Oncology, 660 S. Euclid Ave., Mail Stop 8007-0029-11, St. Louis, MO 63110; email: jdipersi@wustl.edu.
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Healio Interview
Kim MY, et al. Nat Commun. 2022;doi:10.1038/s41467-022-30860-0.
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