Mantle Cell Lymphoma Outcomes May Improve With Bispecific CD20/CD19-targeted CAR T-cell Therapies

Nirav N. Shah, MD

A version of this interview originally appeared on our sister site, OncLive^®.

At the 2023 Transplantation and Cellular Therapy Meetings, follow-up data from the phase 2 cohort of a single-center, prospective, phase 1/2 study (NCT04186520) evaluating the safety and efficacy of LV20.19 CAR in adult patients with B-cell malignancies who progressed on prior therapies were presented. Ultimately, the data showed that those receiving LV20.19 CAR experienced an overall response rate (ORR) of 100% at day 28 (n = 14).¹

Similarly, complete (CR) and partial response (PR) rates were 71% and 29%, respectively. At 90 days, the ORR was unchanged, and the CR rate increased to 92% (n = 11). The median overall survival (OS) and progression-free survival (PFS) were not reached after 22 months of follow-up, nor were any no instances of grade 3/4 cytokine release syndrome (CRS) observed. The rate of grade 3/4 immune effector cell–associated neurotoxicity syndrome (ICANS) was 14%.¹

LV20.19 CAR is a lentiviral bispecific CAR T-cell therapy targeting both CD19 and CD20 B-cell antigens, being assessed for mantle cell lymphoma (MCL) treatment. Thus far, improved responses and favorable toxicity profiles have been observed, suggesting this as a possibly method maximize patient benefit with CAR T-cell therapy, according to Nirav N. Shah, MD, who presented the data at Tandem 2023.

Previously, the safety, efficacy, and optimal dose of LV20.19 CAR was evaluated in a prior phase 1 dose-escalation and -expansion study (NCT03019055) in patients with relapsed/refractory B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia. The trial established the target dose of LV20.19 CAR at 2.5 × 10⁶ cells/kg and showed that the on-site manufacturing and infusion of LV20.19 CAR was safe, effective, and tolerable.²

Shah, who is an associate professor at the Medical College of Wisconsin in Milwaukee, spoke with OncLive, a sister publication of CGTLive, about the choice to evaluate LV20.19 CAR in MCL, key efficacy and safety data from the follow-up study of this agent, and ongoing efforts to potentially expand its use across other B-cell malignancies.

Could you provide background on this phase 2 study of LV20.19 CAR? What prior data led to this trial?

Nirav N. Shah, MD: This is a follow-up study [using] a construct we had initially worked on called zamtocabtagene autoleucel, [or] LV20.19 [CAR]. It’s a dual-targeted CAR T-cell [therapy]. We had previously completed and published a phase 1 [trial, showing] an exciting overall response rate [with this agent], and identifying the safe dose level [in refractory B-cell malignancies]. We developed a follow-up study to better understand this CAR T-cell product.

What was the rationale for the evaluation of LV20.19 CAR in patients with MCL?

This single-center study specifically looked at patients with MCL [and was designed] as a pilot clinical trial. We chose MCL [because] it is a unique non-Hodgkin lymphoma which [has] known high levels of CD20 expression. [In] a disease with high levels of CD20, drugs like rituximab [Rituxan] have been shown to [elicit] survival benefit by targeting CD20. We thought that this CAR T-cell construct would be optimally primed [for MCL] because it targets [both] CD19, which we know is effective in MCL based on prior CAR T-cell approvals, and CD20.

What key efficacy findings from this study were shared at the meeting?

This was a phase 1/2 study [with] a 14-patient, single-stage, design. We based our calculations on the 3-month CR rate in the pivotal [PCYC-1104 trial (NCT01236391)] of ibrutinib [Imbruvica; Pharmacyclics/Janssen Biotech] for relapsed/refractory MCL and targeted a 50% 3-month CR rate. We were going to call this a positive study if we had 6 or more patients who achieved a CR by day 90. We have now achieved that end point.

The ORR at day 28 was 100%, and the majority of those [responses] were CRs. [Specifically], 71% of [responses] were CRs, and 29% were PRs. At day 90, the ORR was still 100%. Some patients converted from a PR to a CR, so the CR rate was 92%. In the phase 2 cohort, we now have 8 patients with a CR at day 90. We do consider this to be a positive clinical trial. We [also] have reasonable follow-up on these patients. [At] a median follow-up of 22 months, there’s been 1 relapse [among] 14 patients.

How did the toxicity profile of LV20.19 in MCL compare with its use in other disease settings?

Overall, the safety profile was in-line with other histologies that we have treated with this product. CRS did occur in 93% of patients. Only 21% of patients had neurotoxicity. Two patients had grade 3/4 ICANS and 1 patient had grade 1/2 ICANS. No patients required intensive care unit–level care in the first 28 days.

We did have 1 nonrelapse mortality. [This] was a high-risk patient who had relapsed [after] prior allogeneic transplant for MCL and then got CAR T-cell therapy. He passed away from gram-negative sepsis at day [46, which was] outside of the dose-limiting toxicity period. Beyond that, [the regimen] was well tolerated, and all [other] patients remain alive.

What are the next steps that are planned for this research?

We’re really excited by these outcomes. The safety profile and efficacy profile of this CAR T-cell product are favorable compared [with] what’s currently available. We launched a phase 2 trial in diffuse large B-cell lymphoma, and I’m working with our partners to codevelop a similar multicenter trial with the CD20/CD19 CAR T-cell product in MCL. That trial is under development now, [and aims] to see if we can [confirm] these single-center results in a multicenter setting.

Is there anything you’d like to note about the use of LV20.19 CAR in B-cell malignancies?

[Although LV20.19 CAR] has different names depending on whether it’s a single-center or industry-sponsored study, we’re fundamentally talking about the same construct. It’s exciting that we’re showing feasibility, efficacy, and safety [with this construct] in different patient populations and in different clinical trials.

What research were you excited to see presented at the 2023 Transplantation and Cellular Therapy Meetings?

Some exciting data [were presented] in the late-breaking abstract session. There’s data coming out about CD22 CAR T cells being given as a second[-line therapy] for patients who have relapsed after CD19-based [therapy]. That’s an area of unmet need, and the data look exciting. The transplant meeting [also showed] exciting data on stem cell and allogeneic stem cell transplant. I [enjoy] gathering live, getting to collaborate with colleagues, and seeing all the cutting-edge data.

Transcript edited for clarity.

Disclosures: Shah disclosed advisory roles with Legend, Epizyme, TG Therapeutics, Kite Pharma, Novartis, LOXO-Lilly Oncology, Janssen, BMS-Juno, Seagen; researcher roles with Miltenyi Biotec and LOXO-Lilly Oncology; consultant roles with Miltenyi Biotec, Lilly Oncology, and Incyte; and a member/founder role with Tundra Therapeutics.

REFERENCES
1. Shah NN, Furqan F, Szabo A, et al. Results from a phase 1/2 study of tandem, bispecific anti-CD20/anti-CD19 (LV20.19) CAR T-cells for mantle cell lymphoma. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 40
2. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569-1575. doi:10.1038/s41591-020-1081-3