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“[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 ques-
tion: How are we going to now activate the immune response in
lymphoma? Clearly, it comes down to: Can we influence an in-
hibitory balance? Can we reverse the T-cell exhaustion? Or, can
we get rid of this inhibitory kind of approach, which is suppress-
ing 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 lym-
phoma (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 pembrolizum-
ab 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 fron-
tier 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 Chil-
dren’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, ex-
pense 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%
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 fur-
ther 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.” ●
March 2018
39