Steven N. Fiering & Sharon Evans (2019) Introduction to thermal therapy
and immunotherapy: at the crossroads of new discovery, International Journal of Hyperthermia, 36:sup1, 1-2,
https://doi.org/10.1080/02656736.2019.1659427
We are very pleased to publish a significant and diverse collection
of primary studies and reviews in this special issue
entitled Thermal Therapy and Immunotherapy: at the
Crossroads of New Discovery. We thank Boston Scientific
Corporation for financially supporting this issue and all
authors for their contributions.
There is a long history of thermal therapy research and
clinical application using both heat and cold but impacts on
the immune system have generally not been the focus of
this research. For most of the twentieth century the immune
system was understood to be important for protecting us
from infectious disease and, when appropriate control fails,
causing autoimmune disease. As the tools of molecular and
cellular biology were applied to the immune system it has
become clear that the immune system is important not just
in infectious disease and autoimmunity, but in almost
every pathology.
Over 120 years ago, studies in patients with cancer done
by William Coley showed that immune stimulation by bacteria
could generate remission in a small but significant fraction
of unresectable metastatic cancers. Coley utilized one of
the few systemic immune readouts available at the time,
fever, as a biomarker of whether the treatment was likely
sufficient. After a century of discussion on what if any role
the immune system plays in cancer, it is now clear not only
that the immune system is an integral aspect of cancer biology,
but that cancer is in part a failure of the immune
response, and most importantly, it is now established that
the immune system can be manipulated to treat cancer. This
is highlighted by the expanding revolution in clinical cancer
immunotherapy with the first wave being antibodies that
block immune checkpoints PD-1 and CTLA4 on T cells.
Within the thermal therapy research community there has
been a distinct change of focus over recent years. With some
notable exceptions, most previous interest was in eliminating
treated tumors with ablative hyperthermia or cryotherapy
with minimal interest in how that local ablation impacts the
systemic antitumor immune response. There are multiple
clinically validated thermal and cryotherapy approaches to
rapidly eliminate treated tumors and they are used daily for
cancer treatment. However, the unmet clinical challenge of
most solid cancers is not individual tumor elimination, it is
systemic treatment to block progression of metastatic disease.
The intersection of physical tumor treatments such as
hyperthermia, cryotherapy and radiation with immunotherapy
is now of considerable interest. This special issue is one
sign of the growing interest in how thermal therapies impact
the immune system and most of the papers are focused on
using thermal therapy as one aspect of systemic immunotherapy
to treat metastatic disease.
There is considerable data that all thermal treatment
modalities of tumors can have a stimulatory effect on the
antitumor immune response by a variety of mechanisms,
including simply releasing tumor antigens from dying tumor
cells. However, on their own, the immune stimulation of
thermal therapies is generally not curative for untreated
tumors, and combination with other immunotherapies is
how thermal therapies are expected to contribute to tumor
immunotherapy. With this perspective comes many questions
that need to be addressed to rationally design such
combinations. Among important questions: what are the
optimal thermal dose parameters and delivery methods;
what are the mechanisms that impact the immune system;
and how best to sequence thermal therapy with other treatments
to generate optimal immunotherapy for cancer.
The issue opens with a review of “Hyperthermia and
immunotherapy: clinical opportunities” by Hurwitz. This
paper gives a broad view of the current state of clinical
hyperthermia for cancer treatment and notes the lack of specific
clinical trials utilizing combination of hyperthermia and
immunotherapy and the importance of initiating
such studies.
It is clear that cryotherapy for cancer, a clinically available
option, is able to support antitumor immune responses.
Baust et al. review the physical and biological parameters of
cryotherapy and how it can generate an “abscopal effect” in
which untreated tumors are reported to shrink through
immune influence. The review explores concepts of how to
optimize that antitumor immune response.
Lin et al. review and explore the important “fever” range
hyperthermia of 39–41C and how that affects the immune
system, particularly in regard to the key step of trafficking of
immune cells into sites of inflammation. One less obvious
but important aspect discussed is that systemic fever range
temperatures can be generated by actual fever or by whole
body hyperthermia, but they have some very fundamental
physiological differences. With fever, the body temperature
set point has been changed to conserve heat and raise body
temperature, the body physiology shifts to cause the warming.
With hyperthermia, the physiological set point is still at
37C and the body attempts to adjust and resist the externally
generated increase in temperature.
This conceptual review that touches on leukocyte trafficking
is followed by a related animal model experimental study
by Ito et al. investigating how local radio-frequency hyperthermia
treatment of tumors influences trafficking of adoptively
transferred T cells into tumors. There is considerable current research focus on adoptive T cell therapy to treat
cancer, however in general, results in solid tumors have
been inconsistent, at least in part because the T cells do not
get into the tumors. The study depends on exceptional skill
with intravital microscopy and includes a clear demonstration
that the addition of hyperthermia changes ineffective adoptive
T-cell therapy into highly a highly effective combinatorial
immune-based therapy.
Combinatorial strategies are the basis of most cancer
therapies and are rapidly expanding within cancer immunotherapy.
Duval et al. explore the immunogenic effects of
combining low doses of both hyperthermia and radiation
and show specific relevant changes of tumor cell gene
expression when both physical modalities are employed as
compared to a single modality. Oei et al. contribute an interesting
in vivo mouse study using a spontaneous metastatic
orthotopic breast cancer model. Treatments were various
combinations of iron-oxide nanoparticle mediated hyperthermia,
radiation, and immune checkpoint inhibiting antibodies.
The results and conclusions are extensive and complex with
some simple takeaways being that heat plus radiation had
very strong local effects and adding immune checkpoint
therapy clearly had the strongest effect on the primary
tumor. However, the impact on spontaneous metastasis,
which was compared to surgery, was more complex and
points the way toward further needed studies.
Singh et al. contribute a study combining focused ultrasound
mediated hyperthermia with CD40 agonist antibody
in a mouse cancer model. The study shows that this combination
improves treatment efficacy through immune mechanisms
and documents a variety of responsive immune
parameters that are mechanistically implicated in that
improved efficacy.
Qiao et al. report on results of a phase I clinical trial in
previously treated patients with a variety of solid tumors.
The study combined moderate temperature hyperthermia
with autologous adoptive T cell therapy and either salvage
chemotherapy or anti-PD-1 antibody therapy. The results
include changes to a variety of immune biomarkers and
show that the combination was safe and generated clinical
responses in some of the patients.
There is more to thermal influences on the immune system
than cancer involvement and Hylander and Repasky
have contributed a forward-thinking review on how temperature
can influence the gut microbiome. There is a rapidly
developing understanding that the huge numbers of microorganisms
we carry have profound influences on our physiology
and pathology, including particularly strong influences
on the immune system. These immune influences are perhaps
best illustrated by the strong associations being
reported on the impact of gut microbiome on development
of autoimmune disease. There are also strong associations
between gut microbiome characteristics and response to
cancer immunotherapy. As outlined in this review, the
impact of temperature on the gut microbiome now has clear
relevance for a number of important topics in biomedical
research and clinical care.
Steven N. Fiering
Department of Microbiology and Immunology,
Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
[email protected]
Sharon Evans
Roswell Park Cancer Institute, Buffalo, NY, USA