Carlos A. Ramos, MD
In phase I results published in the Journal of Clinical Investigation
, researchers have determined that CD30-specific chimeric antigen receptor (CAR) T cells could be used safely and induce durable complete responses in patients with Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL).
Nine patients with relapsed/refractory Hodgkin lymphoma or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) in a dose-escalation study. Patients were infused at 3 dose levels: 2 × 107
(dose level 1), 1 × 108
(dose level 2), and 2 × 108
(dose level 3). No patient received lymphodepleting chemotherapy prior to CD30.CAR-T infusion, and the 7 patients who received previous brentuximab vedotin (Adcetris) discontinued more than 1 month prior to infusion.
Among the 7 patients with relapsed Hodgkin lymphoma, there was 1 complete response (CR) that lasted more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 continued CR that lasted for almost 2 years, and 3 patients with stable disease. Of the 2 patients who did not respond, 1 was alive with disease and 1 died of disease.
Of the 2 patients with ALCL, 1 had a CR that lasted 9 months following the fourth infusion of CD30.CAR-Ts, and 1 patient did not respond but was still alive with disease.
“We have now used this CAR in a phase I dose escalation study in patients with relapsed/refractory CD30+ Hodgkin lymphoma and ALCL malignancies and show, for the first time to our knowledge, the induction of complete response in relapsed/refractory patients with Hodgkin lymphoma or ALCL, even in the absence of conditioning and without significant toxicities,” first author Carlos A. Ramos, MD, Center for Cell and Gene Therapy, Baylor College of Medicine, and coinvestigators wrote.
Researchers infused CD30.CAR-Ts to each patient as a single administration over 2 to 5 minutes. Molecular signals (genomic quantitative PCR for CD30.CAR-Ts were detected in the peripheral blood of all patients by 3 hours after infusion (94 ± 23 copies/μg of peripheral blood mononuclear cell [PBMC] DNA). These signals peaked within the 1 week after infusion in proportion to dose level, with the highest detection at the third dose level (5791 ± 2463 copies/μg of PBMC DNA).
Molecular signals declined over time (106 ± 41 copies/μg of DNA 3 weeks after infusion), but remained detectable for more than 6 months after infusion in 6 patients.
Seven patients received a second infusion of CD30.CAR-Ts. One patient received a total of 4 infusions, which produced only modest expansion of CD30.CAR-Ts in the peripheral blood. Molecular signals were below the threshold needed to detect distinct CAR-Ts by flow cytometry in patients treated at the first and second dose levels, but CD30.CAR-Ts were consistently detectable in the peripheral blood in patients in the dose level 3 group.
Researchers said CD30.CAR-T infusions were well tolerated at all dose levels, and after ≥1 infusions. None of the most frequently reported adverse events (AEs)—fatigue, hyperkalemia, hypokalemia, or transient elevation of aspartate aminotransferase—was considered related to CD30.CAR-T infusion.
After infusion, there were no significant differences observed in white blood cell counts except for a modest reduction in eosinophils, and B and T cell counts remained stable.
No patients developed symptoms consistent with cytokine release syndrome. Researchers noted elevations of inflammatory cytokines, such as IL-6 and TNF-α, which generally coincided with the peak of CD30.CAR-T expansion, but found that the fold increases from baseline were modest. Similarly, they did not observe significant changes in levels of IL-15, IL-7, or IL-2.
Because CD30 is expressed on activated T cells, researchers monitored T cell immunity to viral antigens in all patients before and after infusion of CD30.CAR-Ts. CD30.CAR-Ts did not impair the frequency of T cells reactive to common viral pathogens such as EBV, CMV, adenovirus, or influenza. No patients developed viral infections after receiving CD30.CAR-Ts.
Overall, 33% ± 9% of infused CD30.CAR-Ts expressed PD-1, but researchers observed no correlation between PD-1 expression and CD30.CAR-T expansion or persistence in vivo.
“Our study demonstrates the tolerability, safety, and potential efficacy of CD30.CAR-Ts in CD30+ lymphoid malignancies,” Ramos et al wrote. “Appropriate tumor reduction and lymphodepletion before CD30.CAR-T infusion should enhance their clinical activity without increasing toxicity. Future exploration of the synergy between CD30.CAR-Ts and PD-1/PD-L1 blockade may also prove beneficial.”
Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes [published online August 14, 2017]. J Clin Invest. doi: 10.1172/JCI94306.