Novel CAR T Utility Must Be Confirmed Across Hematologic Malignancies

Craig Sauter, MD

Early data on the use of allogenic and dual-targeted CAR T-cell therapies indicate their potential ability to provide expanded, effective, and more easily accessible treatment options to patients with relapsed/refractory large B-cell lymphoma (LBCL) who progress on CD19-directed CAR T-cell therapy.

Nevertheless, the lack of late-phase data for these products, continued logistical limitations, and questions with treatment selection must be addressed before clinicians can definitively state the effect these options will have on the treatment paradigm, according to Craig Sauter, MD.

“We tend to get excited [about these] early-phase [data], but we know [that] excitement can be blunted in later-phase studies,” said Sauter, who is director of the Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, at Cleveland Clinic in Ohio. “We would need to see those data [and observe] if it moves the needle.”

Efforts to provide next-line CAR T-cell therapies for this patient population have also led to the investigation of CD22-directed therapies. Findings from a phase 1 study (NCT04088890) of CD22-directed CAR-T cell therapy in patients with LBCL were recently presented at the 2023 Transplantation and Cellular Therapy Meetings. The study showed that the product elicited a overall response rate (ORR) of 68% with a complete response rate of 78%.¹

In an interview with OncLive® centered on his presentation at the 27th Annual International Congress on Hematologic Malignancies®, Sauter discussed the common limitations of CAR T-cell therapy through timely referral and the existing questions for patients with LBCL who progress on CAR T-cell therapy. He also discussed the optimal sequencing of traditional vs emerging treatments in the pipeline.

OncLive^®: Regarding your presentation at this year’s meeting, what are the limitations with CAR T-cell therapies in DLBCL? What strategies could be employed to potentially ameliorate them?

Sauter: One of the current practical limitations is availability and timely access to these products, especially in poor-risk disease, as well as early relapse and primary refractory settings.

Timely referral from the outside [could improve outcomes with CAR T-cell therapy]. We know through [previously] presented data that a soberingly [low] fraction of patients who are eligible for this therapy are getting referred, having cells collected for generation, and receiving the therapy. With an aggressive disease, timely administration of this therapy is paramount.

[Additionally, dual-targeted products] can overcome antigen escape and loss in theory. Whether or not that's going to significantly move the needle significantly remains to be seen through carefully conducted prospective studies.

How could the expansion of both autologous and allogenic CAR T-cell therapies maximize the benefit with this treatment in DLBCL?

We want to have both autologous as well as off-the-shelf investigational CAR-modified T-cells available, particularly for patients who had progressed [on] previous CD19-directed CAR T-cell therapy. Having a robust portfolio not just for CAR T cells, but [for] the burgeoning area of BiTEs and other novel agents is imperative for these patients. [Many] successes have been [seen] in the last 3 to 5 years, and we have made leaps [in the treatment of patients with] relapsed/refractory large B cell lymphoma.

Shifting to the 2023 Transplantation and Cellular Therapy Meetings, what presentations were particularly influential and relevant to this space?

The best abstract presentation [was] by Matthew Frank, MD, PhD [of Stanford University, on] the [use of] CD22-directed autologous CAR T-cells in post [CD19-targeted CAR T-cell therapy] failures. [The studyshowed] exciting data, and we're looking forward to having that study open.

What factors should be considered when navigating treatments for patients with LBCL?

The [most important] prognostic factors for early relapse/refractory patients proceeding to CAR T-cell therapy are tumor bulk and tumor burden. [Additionally], there are [several] exciting combination studies [on] bispecific antibodies and ADCs with traditional platinum-containing backbones [in this space]. In my purview, [these regimens] should be considered for optimal debulking prior to CAR T-cell therapy, and optimization of results [with therapy].

Which unanswered questions remain open with optimal sequencing of novel therapeutics in hematologic malignancies?

If second-line platinum-containing salvage therapy is given the community [setting], and a patient clears a PET scan or has a complete metabolic response, [there is] the question of whether consolidation with traditional autologous transplant or newer on-label CAR T-cell therapy is [best].

If a patient achieves a complete metabolic response to platinum-containing salvage therapy, I would personally favor an autologous transplant, because most datasets [show that] at least 60% to 70% of the patients will be cured [with this approach]. We don't have those data with CAR T-cell therapy. There is a pharmacoeconomic consideration for patients who have undergone apheresis and generation of their CAR T-cell products. This is a hotly debated topic of conversation in the field.

What novel CAR T-cell products are gaining traction in DLBCL? What avenues exist for the continued development of novel CAR T-cell products for this space?

The [CD22-targeted] product [is very exciting], particularly if we look at sequencing therapies. Again, most of these [CAR T-cell products] are in early phases, and we need to conduct those studies at a larger scale.

The [most important] and practical avenue [for] clinical investigation is [identifying] how we sequence these therapies. We are [soon] going to have bispecific antibodies [that are] FDA approved along with CAR T-cell therapies, and we already have other targeted agents such as long as loncastuximab tesirine-lpyl [Zynlonta], as well as polatuzumab vedotin-piiq [Polivy]. That should be a focus of clinical investigation because we just don't know the optimal strategy at this point.

If efforts to expand the use of allogenic CAR T-cell therapies are successful, could these products replace the use of traditional autologous CAR T-cell products in practice?

It remains to be seen [whether] off-the-shelf CAR T-cell products [will become a new standard of care]. The question of durability, particularly durability of response, is still [unanswered]. [At the Cleveland Clinic], we're looking forward to results of the [phase 1/2] ALPHA-2 study [NCT04416984], which is [evaluating] an allogenic, off-the-shelf CAR T-cell product that has been [assessed] at many centers, but not in our center.

Clearly access to CAR T-cell therapy is an ongoing issue. [We have good data from] these modified intention-to-treat [ITT] analyses. [However], many patients don't get CAR T-cell therapy in a true ITT [population], because they have rapidly progressive disease and can't access the therapy in a timely fashion. [Therefore,] a successful off-the-shelf product would be [ideal].

Reference

Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B cell lymphoma who relapse after CD19 CAR T cell therapy. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 2.