CAR T-Cell Therapy, Checkpoint Inhibitors Making Waves Across Hematologic Malignancies

Anas Younes, MD

The future is bright for the treatment of patients with hematologic malignancies, most recently due to advancements in chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors, said Anas Younes, MD.

Tisagenlecleucel (Kymriah) was approved by the FDA in May 2018 for use in adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy. This indication includes diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The approval was based on findings from the phase II multicenter, single-arm JULIET trial, in which the CD19-directed CAR T-cell therapy reached an overall response rate (ORR) of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.¹ Tisagenlecleucel was previously approved for use in patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

CAR T-cell therapy is also showing promise in multiple myeloma. At the 2017 ASH Annual Meeting, the BCMA-directed CAR T-cell therapy bb2121 induced complete remissions for 56% of patients with relapsed/refractory multiple myeloma.² This CAR T-cell therapy has achieved a breakthrough therapy designation by the FDA based on these preliminary clinical data.

In addition to CAR T-cell therapies, checkpoint inhibition is also an area that investigators are focusing on in various lymphoma subtypes, said Younes, professor of medicine and chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center.

For example, the combination of the PD-L1 inhibitor atezolizumab (Tecentriq), obinutuzumab (Gazyva), and bendamustine (Treanda) achieved a complete response (CR) in 75% of patients with follicular lymphoma when used as a frontline therapy.³ Additional data from the phase Ib/II trial showed an ORR of 85%, which also included a 10% partial response rate.

OncLive: What is the current state of CAR T-cell therapy in hematologic malignancies?

What about immune checkpoint inhibitors?

In an interview with OncLive, Younes discussed the current and future state of CAR T-cell therapies and immune checkpoint inhibitors in the landscape of hematologic malignancies.Younes: We know that there are CAR products approved for ALL and DLBCL, and the next disease to benefit from this treatment modality is going to be multiple myeloma. There were 2 phase I trials reported at the 2017 ASH Annual Meeting with remarkable response rates. I am talking about a 90% response rate with a high CR rate. Again, with all of these CAR T cells, the length of follow-up is still relatively short, but these high response rates are very exciting. Checkpoint inhibitors have shown a tremendous amount of activity in Hodgkin lymphoma. This is probably the most [immune] responsive cancer—hematologic or solid. For non-Hodgkin lymphoma (NHL), the response rate has been modest with checkpoint inhibitors, whether targeting PD-1 or PD-L1. There is a trend to combine it with other agents, such as small molecules, or moving it to the frontline setting in combination with chemotherapy.

Can you share any other research that you are currently working on?

[In a phase Ib/II trial], we added obinutuzumab and atezolizumab to the standard frontline regimen of bendamustine. The PD-L1 inhibitor is given concurrently with the induction therapy of chemotherapy, but it was also added to the maintenance program for 2 years with obinutuzumab. The response rate is pretty high, and there is also an indication that it is eradicating minimal residual disease (MRD). However, we need long-term follow-up to see how durable these responses are. The way that we are addressing the treatment of lymphoma in general, we are focusing on patient selections and using biomarkers. This is applicable to other types of cancers. We are a little behind compared with other cancers, but we are starting to use genome sequencing data to select patients and further guide therapy. It is a mass, or umbrella, protocol, where we look at several genetic alterations and group them in pathways, select the patient based on these pathways, and treat them with more than one targeted agent based on the biology and mechanism that had been explored, at least in vitro. This is precision medicine; that is one area we are focusing on.

The other area is immunotherapy. CAR T cells are generating a lot of excitement for NHL, ALL, and multiple myeloma. However, checkpoint inhibitors are also being explored in Hodgkin lymphoma. There are combinations with checkpoint inhibitors with small molecule inhibitors, other antibodies, and with chemotherapy.

The third area that we are focusing on is how to apply cell-free DNA, circulating tumor DNA, or MRD as an endpoint in clinical trials to predict cure rate and promote progression-free survival or overall survival.

References

1. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of JULIET: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 577.
2. Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA car t cell therapy. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.
3. Younes A, Burke JM, Diefenbach CS, et al. Safety and efficacy of atezolizumab in combination with obinutuzumab and bendamustine in patients with previously untreated follicular lymphoma: an interim analysis. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 481.