As research into immunotherapy has proliferated, the number of specific approaches within the field has spread beyond the original ideas. Specifically, for the treatment of hematologic malignancies, there are now a wide variety of promising avenues for immunotherapeutic treatment methods. Experts discussed some of these approaches, from the widely heralded PD-1 and PD-L1 blockade to more preliminary research into natural killer cell–mediated therapy, during the Extended Education Session, “Immunotherapeutic Approaches to Treating Hematologic Malignancies,” held on Friday, June 3.
Dr. Philippe Armand
In hematologic malignancies, though, research has not progressed quite as far, though there are a host of checkpoint blockade trials ongoing or planned.
“How do we get to the endgame, where we really define what the appropriate role of these drugs is in hematologic malignancies?” Dr. Armand asked.
Target Hunting With Checkpoint Blockade
He described three possible approaches to this field: target hunting, where drugs are developed to have specific targets in specific malignancies; massive force, where drug targets may be wider or in fact remain unknown; and “teamwork,” where researchers develop the best ways to combine these therapies with other immunotherapies, chemotherapy, or other drugs entirely.
Validating the target-hunting idea, Dr. Armand described the progress with checkpoint blockade and Hodgkin lymphoma (HL). “HL has an unusual biology,” he said, specifically noting the frequent genetic amplification at the 9p24.1 locus. Along with frequent JAK2 amplification and occasionally Epstein-Barr virus infection, this drives expression of PD-L1 and PD-L2 on the surface of tumor cells.
“That suggested that HL might have a genetically determined vulnerability to PD-1 blockade,” Dr. Armand said, which has indeed been borne out in recent studies.
Two phase I trials of nivolumab and pembrolizumab—one published in 2015 and one currently in press—both showed good response rates in patients with relapsed or refractory HL. In the nivolumab study, 23 patients had an objective response rate of 87%, and 26% of patients had a complete response. Similarly, pembrolizumab yielded an objective response rate of 65% in 31 patients with relapsed/refractory HL, and 16% had a complete response.
Dr. Armand noted that it is now also known that this phenomenon is not specific to relapsed/refractory disease. In fact, 99% of patients with newly diagnosed HL had an alteration within 9p24.1. “This is a near-universal abnormality,” he said, making this malignancy uniquely susceptible to PD-1 blockade.
Dr. Armand went on to discuss several other potential targets where checkpoint blockade could reasonably provide good results. For example, primary mediastinal large B-cell lymphoma is the closest genetic cousin of classical HL and also frequently has an alteration at 9p24.1 and the associated overexpression of PD-L1 and P-L2 on the tumor cell surface. Preliminary results of a phase I trial with pembrolizumab were presented in 2015, and though the number of evaluable patients was small, the response rate was promising. The phase II KEYNOTE-170 trial in this malignancy is ongoing.
Diffuse large B-cell lymphoma has proven difficult to treat clinically, and nivolumab yielded disappointing results in this malignancy. But Dr. Armand noted that certain subsets of patients could see benefit with PD-1 and PD-L1 blockade, including those with Epstein-Barr virus.
It is important to note, though, that what Dr. Armand called, “our embryonic understanding of the biology involved” makes progress in this field difficult. There are some malignancies that show high expression of PD-1 and PD-L1 but have not responded to checkpoint blockade. For example, one study of nivolumab in multiple myeloma first presented in 2014 yielded a response rate of 0%, in spite of PD-L1 positivity.
In contrast, other malignancies such as follicular lymphoma have responded to these drugs—a 40% response rate to nivolumab in the same 2014 trial that included patients with myeloma—despite being negative for PD-L1 expression.
“In all, I think this makes target hunting a valiant strategy but an imperfect one,” Dr. Armand said.
Massive Force and Teamwork
Shifting focus to the “massive force” approach, Dr. Armand discussed the use of checkpoint blockade in concert with autologous or allogeneic stem cell transplant. Though there is a rationale for both of these, data is generally limited on its efficacy, and there are risks to consider.
“Checkpoint blockade after [allogeneic stem cell transplant] may be a useful strategy, but is it really what we need now?” Dr. Armand asked. “When we add checkpoint therapy to transplant, we are without a doubt going to increase toxicity.” With other novel therapies and approaches proliferating, this could limit the potential of combining with transplant.
Dr. Armand’s last method for using checkpoint blockade involves combining the drugs with other therapies—the “teamwork” approach to immunotherapy. He noted that checkpoints could be used as an “escape mechanism” for tumor cells, so targeting the checkpoints in parallel with other therapies has a strong rationale.
Positive clinical data on this approach in solid tumors such as melanoma exist, but it is limited in hematologic malignancies. Still, some results have been promising. For example, while nivolumab alone produced no responses in multiple myeloma, a regimen combining pembrolizumab and immunomodulatory therapy with lenalidomide and dexamethasone yielded an objective response rate of 76% in a trial presented in 2015. It is also possible that combining checkpoint blockade with chemotherapeutic agents, radiotherapy, and perhaps other approaches could be effective.
T Cell–Engaging Antibodies
Dr. Max S. Topp
There are a number of possible approaches to targeting these antigens, including with chimeric antigen receptor (CAR) T cells. Dr. Topp described these as “personalized serial killers.” Gene transfer technology is used to express CARs on T cells, which confers novel antigen specificity; the CAR T cells seek out tumor cells and lyse them. Every T cell modified in this fashion could become a cancer cell serial killer.
Another way to direct T cells toward tumor cells is with bispecific T-cell engager technology. Dr. Topp explained that blinatumomab, the most prominent of these engagers, allows T cells to recognize a surface antigen—again, the commonly expressed CD19 antigen—and kill them. A single T cell modified by blinatumomab can kill up to 10 tumor cells before needing to proliferate again, Dr. Topp said.
Blinatumomab has shown promise in patients with ALL, even in those deemed at high risk of relapse based on minimum residual disease (MRD). In a phase II trial of 21 patients by Dr. Topp’s group published in 2011, most patients had very high pretreatment MRD levels, meaning they were very close to relapsing. Even in this group of patients, 80% achieved a molecular complete response with blinatumomab. The other 20% had stable disease, and no MRD increase was seen during treatment.
In a 2014 dose-finding phase II study of adult patients with relapsed/refractory, MRD-positive ALL, he said cytokine-release syndrome emerged as a problem at the lowest blinatumomab dose given. By adding dexamethasone, however, this problem disappeared. Responses in this trial were again very promising, with 69% of 36 patients achieving a complete response or complete response with partial hematologic recovery.
In another study of blinatumomab in patients with Ph-negative relapsed/refractory ALL, it was again patients with MRD-negative disease who had superior survival, Dr. Topp said. He added the optimal position of this agent in the frontline treatment of ALL remains unknown at this point.
“Is it more than just blinatumomab in this context,” Dr. Topp asked. The antigen-targeting approach could yield many other constructs as potential agents. And it is also not just CD19; trials targeting CD20, CD30, CD33, and others are ongoing.
Natural Killer Cell Approaches
T cells may be able to transform into serial killer cells, but they aren’t the only killers. Veronika Bachanova, MD, of the University of Minnesota, discussed the concept of harnessing natural killer (NK) cells for cancer therapy.
“While T cells have antigen specificity, NK cells are not antigen-specific,” she said. They express CD16, which can mediate the killing of antibody-coated cells. “In order to understand the clinical applications of NK cells, we need to recognize how we can turn NK cells on,” Dr. Bachanova said.
The most powerful method that turns NK cells on, she said, is cytotoxicity, either natural or antibody-dependent cellular cytotoxicity. Both of these processes can be enhanced with cytokines, specifically interleukin-15 and interleukin-2.
Autologous NK cells are unable to kill tumor cells, however, because HLA downregulation is variable and incomplete. With donor NK cells, however, KIR-HLA mismatch is common, which can mediate the targeted killing of tumor cells. Adoptive transfer of haploidentical human NK cells in acute myeloid leukemia has been explored, but Dr. Bachanova called this therapy “cumbersome.”
Dr. Carl H. June
“Where is the NK cell therapy field going? Many groups are actively searching and researching NK cell biology,” Dr. Bachanova said. Others are working on refining the NK cell product, and others have different approaches entirely. “We need to better understand the host microenvironment in order to be more successful in immunotherapy.”
CAR T Cells and Next Steps
Carl H. June, MD, of the Abramson Cancer Center of the University of Pennsylvania, discussed the current state of cellular therapy for hematologic malignancies. Synthetic biology represents a particularly interesting interdisciplinary field, and some modern approaches such as gene editing with CRISPR/Cas9 could allow T cells to be designed to be resistant to hostile environments, among other things.
CAR T cells, Dr. June said, also represent an example of synthetic biologic approaches. A variety of trials now use CAR T cells in hematologic malignancies, and he stressed that though safety concerns regarding engineered cells are often raised, no such signals have emerged.
The field is also growing rapidly: as of this month, more than 100 trials were registered with ClinicalTrials.gov with the search term “chimeric antigen receptor,” and Dr. June said that by next year China will likely overtake the United States with dozens of such trials.
“We will soon be entering an era where we have a number of tools for cancer therapy,” Dr. June said. “Our biggest challenge will be learning how to use these in combination.”
– Dave Levitan