Immunotherapy: Exploring the Next Frontier for Non-Hodgkin Lymphoma Treatment

When the U.S. Food and Drug Administration approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel for the treatment of relapsed or refractory B-cell lymphoma, it signaled that the field of immunotherapy was experiencing rapid growth. In a presentation at the 2017 ASH Annual Meeting, experts gathered to discuss “The Expanding Role of Immunotherapy in Non-Hodgkin Lymphoma,” from future directions for T-cell therapies in lymphoma to developing new agents to exploit the tumor microenvironment.

Finding Your Niche

In reviewing the biology of the microenvironment across histologic subtypes of non-Hodgkin lymphoma (NHL), Karin Tarte, PhD, of Université de Rennes in France, argued for the crucial role that the “organized, highly connected cell network” of the microenvironment plays in growth and development of lymphoma.

First, she provided a brief overview of the tumor niche concept. The niche is composed of “heterogeneous cell subsets that all display specific gene-expression profiles and functions,” she said, and together comprise a “dynamic ecosystem [that] relies on the continuous co-evolution of the malignant cells and their niche.”

“Each subtype of tumor cells will create its own supportive microenvironment,” Dr. Tarte explained. In follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), for instance, “the good guys” of tumor immunity found in their microenvironments include loss of antigen presentation and immunosuppressive context.

“However, [in terms of] tumor-supportive signals, FL and DLBCL are quite different,” she said. “Both require activation of B-cell receptor, but FL is one of the best models of a strong dependence to a specific niche, in this case a germinal center-like niche,” Dr. Tarte said. “Conversely, it is proposed that there is a less preeminent supportive microenvironment in DLBCL.”

Unfortunately, she added, “these ‘good guys’ are essentially not efficient, since tumor cells develop a lot of mechanisms to escape immune response.” The “escape routes” include evading immune cell recognition and triggering T-cell exhaustion.

In FL, “the bad guys” of the B-cell NHL tumor niches include T follicular helper and macrophages that produce chemokines or growth factors that promote tumor survival and activate B cells, she explained. “What is interesting is that all the cells of the microenvironment could interact with each other, and stromal cells not only have a direct effect on the B-cells, they are also able to recruit the other supportive cells of the microenvironment,” Dr. Tarte said.

Next, Dr. Tarte examined the potential clinical impact of the tumor microenvironment, asking whether the tumor niche is a source of clinically relevant biomarkers or new therapeutic targets. There have been numerous proposed prognostic biomarkers, she noted, but there is a need for new biomarkers that are predictive of drug response and that fully integrate microenvironment heterogeneity.

“In addition, I think we should consider disrupting B-cell supportive signals together with the stimulation of anti-tumor immune response. The question would be what kind of molecules, and what kind of associations?” Dr. Tarte noted.

Conversely, future investigations also will have to answer the question of how treatments impact the tumor niche. Dr. Tarte said that she anticipates the greater availability of tools to decipher cell heterogeneity that could provide clues on the “crosstalk” between malignant B cells and their niches.

Harnessing the Power of the Immune System

Stephen Ansell, MD, PhD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, expanded on Dr. Tarte’s presentation, examining how researchers and clinicians could use insights into the tumor microenvironment to improve immunotherapies for patients with NHL.

“[We need] a cytotoxic T cell that effectively can target and kill a malignant lymphoma cell, but there are a variety of different cells … conspiring together to inhibit this effective anti-tumor response,” Dr. Ansell explained, highlighting one of the primary challenges of immunotherapy development.

These immunologic barriers that prevent effective therapy include increased regulatory T cells, increased exhausted T cells, and increased PD-L1 and PD-L2 expression in lymphoma. Dr. Ansell also mentioned that “many immune-active molecules and cytokines that are present in the patient or present in the tumor, actually induce exhaustion.”

“With all of this in mind, we need to ask ourselves a question: How are we going to now activate the immune response in lymphoma? Clearly, it comes down to: Can we influence an inhibitory balance? Can we reverse the T-cell exhaustion? Or, can we get rid of this inhibitory kind of approach, which is suppressing the immune system, and thereby liberate the immune system to target the malignant cell?” he remarked.

Dr. Ansell focused on two methods for preventing immune suppression or exhaustion: blocking the inhibitory signals CTLA-4 and PD-1. While research demonstrated that blocking CTLA-4 (via ipilimumab) was a tolerable approach, the agent induced only modest activity. Despite more success with PD-1 signaling (via nivolumab and pembrolizumab) in Hodgkin lymphoma (HL), the efficacy of this approach varies in NHL.

“Optimizing immune function is the new therapeutic frontier in lymphoma.”

—Stephen Ansell, MD, PhD

Response appears to depend on the NHL subtype, Dr. Ansell noted. For instance, response rates were “encouraging” or “promising” in small studies of pembrolizumab-treated patients with primary mediastinal B-cell lymphoma, natural killer/T-cell lymphomas, primary central nervous system lymphoma, or mediastinal gray-zone lymphoma; in other B-cell lymphomas, responses to nivolumab were “less impressive.”

Other investigational agents are taking a different route, he explained: directly activating immune cells. “Simply activating cells might be insufficient,” he said, according to modest activity seen with the anti-CD27 agonist antibody varlilumab and the anti-CD40 monoclonal antibody dacetuzumab in small trials.

Researchers are now investigating whether combining these approaches would improve immune response rates. Experiences with the combination of checkpoint inhibitors nivolumab and ipilimumab were disappointing, but combining pembrolizumab with rituximab led to high overall response and complete response (CR) rates. “Clearly, we need to understand these [combinations] better,” he said. “If these combinations bear out in the future, that would be very exciting.”

“Optimizing immune function is the new therapeutic frontier in lymphoma,” Dr. Ansell concluded. “We’ve seen exciting results in HL, we’ve seen some exciting results in some subsets of NHL, and there are now multiple new agents that allow us to block the inhibitory signal or provide an agonistic signal.” Future investigations, however, will need to answer questions about how to combine these agents and in which diseases these approaches would be most effective.

Beyond CAR T-Cell Therapies

CAR T-cell therapies have stolen the spotlight in lymphoma and other malignancies, but Catherine Bollard, MD, of the Children’s National Health System in Washington, DC, reviewed the other forms of T-cell therapy under investigation – and how they may overcome some of the limitations of CAR T-cell constructs.

“We have many different T-cell approaches to attack the tumor cell,” she said, including donor lymphocyte infusion, multi-antigen-specific T cells, and T-cell receptor-transduced T cells. And, while larger trials have now shown “the remarkable ability of CD19-directed CAR T cells to induce CRs,” there are issues that need to be addressed, Dr. Bollard noted. Issues of toxicity management, the complexities of gene modification, expense and reimbursement issues, and the possibility for immune escape through antigen loss have compelled investigators and clinicians to search for alternatives.

Dr. Bollard focused on two approaches:

  • Targeting Epstein-Barr virus (EBV)-positive lymphomas (EBV-specific cytotoxic T lymphocyte): This approach has been “highly successful,” she said, with durable response rates observed in post-transplant lymphoproliferative disease. Because EBV antigens are expressed by 20 to 40 percent of lymphomas, they represent potential targets for T-cell immunotherapy.
  • Targeting EBV-negative lymphomas: For lymphomas that don’t express this antigen, “we can use the same manufacturing platform, just using different peptides and replacing the EBV-targeting antigens with tumor-associated antigens.”

Each of these approaches is cheaper, requires less regulatory oversight, and has more favorable toxicity profiles than CAR-T, Dr. Bollard summarized. “However, there is efficacy seen using both approaches, and the CAR-T cell approach is certainly further along with respect to receiving licensure.”

“It is still unclear where it will be best to use [each type of] T-cell therapy, whether it be upfront, whether it be as a bridge to transplant, or a salvage to transplant,” Dr. Bollard concluded. “But, I agree with Dr. Ansell that we’re living in exciting and interesting times when we can harness the power of immune therapy.”