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Natalie Grover, MD, Talks Anti-CD30 CAR-T Therapy for Hodgkin Lymphoma

 

Natalie Grover, MD, Assistant Professor of Medicine, Division of Hematology, University of North Carolina School of Medicine, discusses her study on anti-CD30 CAR-T therapy for patients with relapsed/refractory Hodgkin lymphoma.

Transcript

My name is Natalie Grover. I'm an Assistant Professor in the Division of Hematology at the University of North Carolina and the Clinical Director of the Cell Therapy Program in the Lineberger Comprehensive Cancer Center at UNC.

CAR-T cells targeting CD19 have shown remarkable efficacy in B‑cell lymphomas. This has sparked interest in exploring other targets in lymphoma. CD30 is universally expressed in Reed‑Sternberg cells. These are the malignant cells in classical Hodgkin lymphoma.

In addition, targeting CD30 has minimal on‑target, off‑tumor toxicity because it has low expression in normal tissue. Its efficacy and safety as a target has also been demonstrated by the success of the drug brentuximab vedotin.

Although the majority of patients with Hodgkin lymphoma are cured with first‑line therapy, a proportion of patients have relapsed or refractory disease, and prognosis is worse for those patients.

Phase 1 trial of CD30‑directed CAR-T cells was performed by Dr Savoldo and Dr Ramos. In this trial, patients did not get lymphodepletion or a preparative chemotherapy prior to receiving CAR-T cells.

CD30‑directed CAR-T cells were found to be safe, with no dose‑limiting toxicities, including cytokine release syndrome or neurotoxicity, but the responses seen in that trial were limited. Lymphodepletion has been shown in other types of CAR-T cells to make room for CAR-T cells and allow for an ideal cytokine milieu for CAR-T cell expansion and persistence.

Our trial of CD30‑directed CAR-T cells used the same construct as used in that previous trial, but added lymphodepletion prior to diffusion of CAR-T cells. Our main hypothesis was that CD30 CAR‑T cells would be safe and effective in treating patients with relapsed or refractory Hodgkin lymphoma.

We treated adult patients with relapsed or refractory Hodgkin lymphoma with CD30‑directed CAR-T cells. We treated 41 patients at 2 sites at UNC and Baylor. These were heavily pretreated, with a median of 7 prior lines of therapy.

We showed that administering CAR-T cells after lymphodepletion that contained the drug fludarabine produced a high response rate of 72%, with 59% complete response rates with some durable responses seen.

In addition to being effective in patients who have been heavily pretreated, we also found that this was safe with minimal toxicity seen. Less than a quarter of the patients had cytokine release syndrome. It was all grade 1 and it self‑resolved. We didn't see any neurotoxicity.

CD30‑directed CAR-T cells have promising clinical activity in relapsed or refractory Hodgkin lymphoma with a good safety profile. This treatment should be explored further in larger trials.

There is currently a multisite phase 2 trial hoping to be a registration trial of CD30 CAR‑T cells that will be open in the US and internationally. This treatment is generally easy to give and patients can be treated as outpatients.

Our group at UNC is also working on several projects to further expand on the current research. Although the responses in the trial were high, we are working to further improve on the product to increase the response rates and also the duration of responses. We currently have a clinical trial of CD30 CAR‑T cells that co-express CCR4.

We know that the Hodgkin Reed‑Sternberg cells in Hodgkin lymphoma produce a chemokine such as TARC and MDC. These findings were also confirmed in our clinical trial. These chemokines attract suppressive cells that express their cognate receptor, CCR4.

Our initial CD30 CAR‑T cells do not express CCR4. In preclinical studies led by Dr. Savoldo, CD30 CAR‑Ts that co-express CCR4 show improved trafficking and anti‑lymphoma activity compared to CD30 CAR‑Ts that did not express CCR4.

We currently have a phase 1 clinical trial of CD30 CAR‑Ts enhanced with expression of CCR4. Our hypothesis is that this will improve homing to the tumor site.

CD30 CAR‑Ts also express PD‑1, so they may be susceptible to the PD‑L1 inhibition exerted by Hodgkin Reed‑Sternberg cells in a tumor microenvironment. We're also interested in combining CD30 CAR‑Ts with checkpoint inhibitors to build on that.

Finally, we have a larger trial investigating CD30 CAR‑T cells in other lymphomas that express CD30, specifically T‑cell lymphomas.

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