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The 2022 Tandem Meetings | CD30-directed CAR-Ts co-expressing CCR4 in R/R HL and CD30+ CTCL
Natalie Grover, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, discusses the rationale and results of a Phase I trial evaluating the safety and efficacy of CD30-directed CAR-Ts co-expressing CCR4 in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) and CD30+ cutaneous T-cell lymphoma (CTCL) (NCT03602157). Dr Grover explains that despite the efficacy of CD30-directed CAR-Ts, many patients still relapse. This trial was based on the idea that CD30 CART-s co-expressing CCR4 could increase the efficacy of CAR-Ts by enhancing trafficking to the tumor site. The trial reported high response rates in patients with HL and no significant dose-limiting toxicities. Moving forward, the trial found that lower baseline metabolic tumor volume was associated with prolonged progression-free survival (PFS). This study confirms the safety and promising efficacy of CCR4.CD30-directed CAR-Ts in R/R HL and provides proof of concept for future modifications of CAR-Ts to improve localization to tumor sites. This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.
Transcript (edited for clarity)
So CD30 CAR-Ts have shown really promising results for patients of relapsed/refractory Hodgkin lymphoma, but many patients still relapse. So we were looking in ways to further improve the efficacy of CD30 CAR-Ts. One possible way of improving the efficacy may be enhancing trafficking to the tumor site. And that could potentially give CD30 CAR-Ts increased opportunities to eliminate tumor cells before some of the more inhibitory mechanisms become predominant...
So CD30 CAR-Ts have shown really promising results for patients of relapsed/refractory Hodgkin lymphoma, but many patients still relapse. So we were looking in ways to further improve the efficacy of CD30 CAR-Ts. One possible way of improving the efficacy may be enhancing trafficking to the tumor site. And that could potentially give CD30 CAR-Ts increased opportunities to eliminate tumor cells before some of the more inhibitory mechanisms become predominant. And as we know, the Reed-Sternberg cells, which are the malignant cells of Hodgkin lymphoma, produce chemokines, such as TARC, and these chemokines attract suppressive cells, type 2 helper T-cells, and regulatory T-cells. And those cells express the TARC-specific chemokine receptor CCR4. So our thought is that this clinical trial looks at testing CD30 CAR-Ts, with forced expression of CCR4, with the hope that these CD30 CAR-Ts can have improved migration to the tumor site.
So this is a Phase I clinical trial for patients with relapsed/refractory classical Hodgkin lymphoma, adult patients. And also, we also included patients of CD30-positive continuous T cell lymphoma, because of the thought that the CCR4 will improve trafficking to the skin as well. And these patients were treated with CD30 CAR-Ts, which pre-co-expressed CCR4. And we presented data on 13 patients, 11 patients with Hodgkin lymphoma, and 2 patients with cutaneous T-cell lymphoma. And these are very heavily pretreated patients – had a median of five prior lines of therapy. We didn’t see significant toxicity, we didn’t see any dose-limiting toxicities. And only 3 patients had cytokine release syndrome. Two of them were grade 2 and one was grade 1, and this was all, the two grade 2 cytokine release syndrome was manageable with tocilizumab.
And we also showed really high response rates. So the patients with Hodgkin lymphoma, all the patients with Hodgkin lymphoma responded. Eight had complete responses and 3 had partial responses. And we had, out of the patients with cutaneous T-cell lymphoma, we only treated 2 patients today, and one patient had stable disease, and one patient had progressive disease. And we’ve also seen the follow-up is still short, but we’ve also seen some durable responses, including one patient who was still in remission at 3 years post-treatment.
So basically, we show that CD30 CAR-Ts co-expressing CCR4 are safe, and they have promising efficacy in patients with relapsed/refractory classical Hodgkin lymphoma. And we even saw responses at those lowest dose level, and this suggests that early tumor homing driven by CCR4 expression may allow CAR-Ts to exploit their anti-tumor potential. And this is also a proven concept for future modification of CAR-Ts to improve their localization to disease sites.
We have looked at our prior clinical trial of CD30-directed CAR-Ts to help determine what factors might be associated with more prolonged progression-free survival. And we looked at several different factors, including bridging therapy, and response to bridging therapy, and CAR-T expansion and persistence. And actually, in our trial, we did not find that any of these factors was associated with progression-free survival. The one factor that we found that did seem to be associated with progression-free survival was baseline metabolic tumor volume. So patients who had higher metabolic tumor volume at the time prior to lymphodepletion had had a shorter progression-free survival compared to patients who had a lower metabolic tumor volume.