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FEATURES
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 con-
cept. 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 microenvi-
ronments include loss of antigen presentation and immunosup-
pressive 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 de-
pendence 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.”
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Focus on Lymphoma & Myeloma
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 mi-
croenvironment 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 bio-
markers, she noted, but there is a need for new biomarkers that
are predictive of drug response and that fully integrate microen-
vironment 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 mole-
cules, 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 deci-
pher cell heterogeneity that could provide clues on the “cross-
talk” 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 pre-
sentation, examining how researchers and clinicians could use
insights into the tumor microenvironment to improve immuno-
therapies for patients with NHL.