ASH 2014 Preview: Checkpoint Inhibition, CAR Modified T Cells, and Novel Therapies

Marcel R.M. van den Brink, MD, PhD

The top research being presented at the 2014 American Society of Hematology (ASH) Annual Meeting will focus on immunotherapies and novel agents, according to Marcel R.M. van den Brink, MD, PhD, head of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center (MSK).

In an interview with OncLive, van den Brink highlighted five of the most compelling studies being presented at the meeting from researchers at MSK. Altogether, over 75 papers from faculty at MSK were selected for oral presentation during the ASH meeting, including those focused on chimeric antigen receptor (CAR)-modified T cells, immune checkpoint inhibitors, and novel agents.

The first abstract noted by van den Brink focused on results from the randomized AETHERA study that examined brentuximab vedotin as a treatment for patients with Hodgkin lymphoma who were at risk of progressing following an autologous stem cell transplant (ASCT).

Brentuximab vedotin is a novel antibody-drug conjugate targeted against CD30 and was approved by the FDA as a treatment for patients with Hodgkin lymphoma following ASCT in August 2011. The accelerated approval was based on a single-arm multicenter clinical trial that enrolled 102 patients.

The goal of the large phase III trial was to evaluate whether early treatment with brentuximab vedotin post-ASCT could prevent progression in patients with Hodgkin lymphoma. Furthermore, results from the AETHERA trial could confirm the efficacy of brentuximab vedotin in patients with Hodgkin lymphoma and provide evidence for a full FDA approval.

"We're very curious what these results will be," van den Brink said. "This study was picked as a highlight of ASH, so at this meeting we will hear what the final outcomes are."

Findings from the AETHERA trial (abstract 673) are being presented by Craig H. Moskowitz, MD, who will also describe findings from a phase Ib study examining the PD-1 inhibitor pembrolizumab in patients with Hodgkin lymphoma following progression on brentuximab vedotin (abstract 290).

"This anti-PD-1 antibody has now been tested in a phase I study for relapsed Hodgkin's lymphoma and has shown that it is relatively safe. In these early studies, there is some positive data that it is working," van den Brink said. "At this meeting, we're going to hear the latest update on how well this new strategy for dealing with relapsed Hodgkin's lymphoma is going to work."

Immune checkpoint inhibitors have generated excitement across a variety of settings, including hematologic malignancies. On September 4, 2014, pembrolizumab became the first PD-1 inhibitor to gain approval in the United States as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies.

In hematologic malignancies, the PD-1 inhibitor nivolumab has demonstrated promise in patients with Hodgkin lymphoma, earning the agent a breakthrough designation in May 2014. This designation was for the treatment of patients with Hodgkin lymphoma following ASCT and brentuximab vedotin.

While established and approved agents are expected to attract attention at the ASH meeting, novel agents are also on the horizon for patients with hematologic malignancies, van den Brink noted.

Findings from a phase I study on the first-in-class IDH2 inhibitor AG-221 will be presented at the meeting by Eytan M. Stein, MD (abstract 115). AG-221 is an orally available, selective, potent inhibitor of mutated IDH2, which is being evaluated for patients with AML who have an IDH2 mutation. In April, data were announced at the 2014 AACR Annual Meeting that showed that AG-221 demonstrated responses in six out of seven AML patients (86%).

"This drug will block IDH2 and, by this way, block the process of epigenetic changes that are the result of a high level of this enzyme in these cancer cells," van den Brink said. "This is a phase I study and it shows the drug is relatively safe. Even in the early data, it shows already that in about 40 patients that 20 have responses, which is very rare in a phase I study."

The final abstracts spotlighted by van den Brink focused on CAR T cell therapies, specifically those geared toward CD19 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). These therapies are manufactured through the genetic modification of autologous T cells to express a CAR.

"At this meeting we're going to give an update of the very promising results for CAR T cells for ALL," van den Brink said. "What we're showing now already, but we're going to see the latest data at the ASH meeting, is that 18 of 20 patients with high-risk ALL can be brought back into a complete remission with these CAR modified T cells, which can function as a bridge to allogeneic stem cell transplant."

CAR T cell therapies generated excitement at the 2013 ASH Annual Meeting and have continued to show impressive results over the past year. In July 2014, the first CAR T cell therapy (CTL019) was granted a breakthrough therapy designation from the FDA. On November 24, 2014, the CAR T cell therapy JCAR015 also received this designation for patients with ALL. Juno Therapeutics and MSK are codeveloping this therapy.

"At this meeting, we're going to hear what the outcome are with this first phase I study to use CAR T cells after an auto transplant for CD-positive lymphoma," van den Brink noted.

Jae H. Park, MD, will present updated findings for the CAR T cell therapy in ALL at the meeting (abstract 382). Another study will focus on the addition of a CAR T cell therapy to ASCT in patients with NHL, described van den Brink (abstract 677).

The leading adverse event of high concern with CAR-modified T cells has been cytokine release syndrome. Given the mechanism of action, this adverse event is thought to indicate that the treatment is working. In early April 2014, five early-phase clinical trials exploring CAR T-cell therapies were suspended temporarily to adjust protocols to manage the occurrence of severe cytokine release syndrome.

"Early data are going to be shown for about 6 patients [with NHL]," van den Brink said. "We see the same types of toxicities that we have seen so far with the CAR T cells, which is specifically a cytokine storm. We have developed the protocols to deal with that."

In a report at the 2014 AACR Annual Meeting, researchers noted that severe cytokine release syndrome could be detected using a readily available laboratory test that analyzes serum C-reactive protein. Moreover, they noted that once detected, the adverse event could be adequately treated using corticosteroids or interleukin-6 receptor blockade.

These five studies, plus more, will be discussed December 6-9, 2014, at the Moscone Center, San Francisco, California.

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