Immunotherapy Combinations Show Promise for Blood Cancers

Theodore Bosworth


April 30, 2018

Clinical trials with immunotherapy combinations are expanding rapidly, and it is easy to envision profound antitumor effects. Unlike the incremental improvements in progression-free survival seen with novel cytotoxic drug combinations, immunotherapy combinations hold the potential to be a knockout punch.

Given that cures, or at least apparent cures, are already being seen with single-agent immunotherapy, it is reasonable to speculate that durable complete remissions might be achieved in a larger proportion of patients when a second or third mechanism is added.

But there is a flip side, according to Donna Przepiorka, MD, PhD, a medical officer with the Division of Hematology Products of the US Food and Drug Administration, Rockville, Maryland. Our understanding of the risks involved in disturbing immune function is incomplete, and there is the potential for catastrophic events. The goal is to increase the proportion of patients who benefit from the extraordinary responses that these therapies are already achieving; however, the risks are large.

The term "immunotherapy" can be applied to an array of therapeutics ranging from immunomodulatory drugs and monoclonal antibodies to vaccines, bispecific T-cell engagers, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. The strategies are almost limitless and include combining any of the above with each other as well as with cytotoxic drugs or small molecule inhibitors—work that is already well under way. In the hematologic cancers, some of the most exciting combination data were presented at the American Society of Hematology (ASH) meeting in December 2017.

There has been promise and disappointment thus far, according to Przepiorka, who focused on three major strategies during a special session at the ASH meeting on how immunotherapies might best be combined. The first is to substitute an immunotherapy for one or more drugs in a cytotoxic combination to improve efficacy or render the combination more tolerable, or both.

The second two approaches are conceptually more appealing because they eliminate cytotoxic therapies altogether. One is to combine an immunotherapy with a targeted agent, such as a tyrosine kinase inhibitor (TKI). The other is to add two or more immunotherapies together.

Immunotherapy Substitution

The phase 3 ECHELON trial is perhaps the most significant example of the first of these three strategies. In this trial, the immunotherapy brentuximab vedotin was substituted for bleomycin in the classic ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen.[1] The randomized trial was conducted in patients with previously untreated stage III or IV Hodgkin lymphoma. Relative to ABVD, AVD plus brentuximab vedotin, which combines an anti-CD30 antibody with a microtubule-disrupting agent, delivered a greater progression-free survival at 2 years while providing a more favorable tolerability profile.

Eliminating Cytotoxic Agents

As examples of the second strategy, two studies tested a chemotherapy-free regimen with the bispecific T-cell engager blinatumomab plus a TKI in heavily pretreated acute lymphoblastic leukemia (ALL). Although each study was small, response rates were impressive with relatively little toxicity, emphasizing the promise of this approach.

In one study, eight of the 13 patients, all of whom had previously treated relapsed Philadelphia chromosome-positive ALL, received blinatumomab with the TKI ponatinib.[2] The remainder received blinatumomab with dasatinib or bosutinib. After a median of two cycles, complete molecular responses were achieved in 10 (77%) of the patients.

Although there were three cases of cytokine release syndrome in this series, all were grade 2, reported the lead investigator, Rita Assi, MD, a fellow at the University of Texas MD Anderson Cancer Center in Houston. She suggested that this approach builds on the single-agent activity of blinatumomab, which binds to cytotoxic T cells and to CD19 on ALL cells in order to deliver an immunologic attack.

The response rates were equally impressive in the second study, which evaluated blinatumomab plus a TKI in 11 patients with relapsed/refractory ALL.[3]

After a single cycle of blinatumomab plus a TKI (dasatinib for the majority of patients, although others were used), a complete remission was achieved in 10. Of the six patients who have gone on to a stem cell transplant, one so far has achieved a cytogenetic complete remission. According to Andrew N. Sokolov, MD, of the National Research Center for Hematology in Moscow, Russia, the combination of blinatumomab and a TKI, which was delivered in an outpatient setting, was well tolerated. There were adverse events, including hypogammaglobulinemia and a high prevalence of cytomegalovirus infection, but these rates of response are unprecedented, and Sokolov, like Assi, highlighted the appeal of omitting chemotherapy entirely in advanced disease.

Combining Immunotherapies

For the third strategy—combining two or more immunotherapies—there is a particularly strong rationale for using checkpoint inhibitors with something else. Although checkpoint inhibitors as single agents have repeatedly achieved durable clinical remissions in a variety of cancers, only a limited proportion of patients respond. In other cancers, checkpoint inhibitors generate relatively little antitumor effect despite the theoretical advantages of their mechanism of action.

As an example, checkpoint inhibitors, such as nivolumab, have been disappointing in multiple myeloma. However, it may be a candidate for immunotherapy combinations, according to Sharmilan Thanendrarajan, MD, of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock.

Lead author of a single-center study in which nivolumab was combined with a variety of immunomodulatory agents, such as lenalidomide, and with the anti-CD38 monoclonal antibody daratumumab, Thanendrarajan provided data supporting this approach in highly advanced refractory disease.[4]

In this study, which evaluated 12 patients with multiple myeloma who had a median of six lines of prior therapy, there were no responses in the four patients who received nivolumab alone. In contrast, patients receiving nivolumab with an immunomodulating agent, such as lenalidomide or the monoclonal antibody daratumumab, often achieved stable disease, and several achieved an objective response. Thanendrarajan called side effects "manageable" in this proof-of-principle evaluation.

These and other small patient series support the concept of combining immunotherapies, but Przepiorka said that a systematic approach, preferably pursuing strategies with a rationale for additive or synergistic effect, are essential for moving this line of investigation forward. For example, she suggested that combining checkpoint inhibitors, which inhibit the signal with which tumors hide from the immune system, with an immune stimulator, such as a vaccine or epigenetic modifier that upregulate antigen expression, is of particular interest.

Pushing the Envelope

In late-stage, poor-prognosis cancer, there is a willingness to push the envelope with immunotherapy combinations. One small study at the 2017 ASH meeting tested the safety of using a checkpoint inhibitor and a CAR T-cell therapy together. In this study, called ZUMA-6, the anti–PD-L1 antibody atezolizumab was combined with an anti-CD19 CAR T-cell construct axicabtagene ciloleucel in patients with aggressive diffuse large B cell lymphoma.[5]

Side effects were significant, including grade 3 or higher encephalopathy in four of the six patients treated, but none were fatal and these were ultimately characterized as "manageable." In a population with up to four prior lines of therapy, diminishing options, and a poor prognosis, the objective response rate was 100%. According to the lead author, Frederick L. Locke, MD, of the Moffitt Cancer Center in Tampa, Florida, there are plans to move to a phase 2 study.

Relative to cytotoxic therapies, immunotherapies represent a precision approach to eliminating malignant cells. The well-documented disease-free remissions achieved with checkpoint inhibitors and CAR T-cell therapies have provided vivid evidence that this strategy is viable. The next step is developing protocols that expand the pool of responders. Experts such as Przepiorka see great promise in the combinations currently being tested. Now that the clinical trials have begun, the clinical science may evolve quickly.


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