Mark D. Hurwitz (2019) Hyperthermia and immunotherapy:
clinical opportunities, International Journal of Hyperthermia, 36:sup1, 4-9,
Hyperthermia holds great promise to advance immunotherapy in the treatment of cancer. Multiple trials have demonstrated benefit with the addition of hyperthermia to radiation or chemotherapy in the treatment of wide-ranging malignancies. Similarly, pre-clinical studies have demonstrated the ability of hyperthermia to enhance each of the 8 steps in the cancer-immunotherapy cycle including stimulation of tumor-specific immunity. While there has been an extensive recent focus on augmenting
immunotherapy with radiation, surprisingly to date, there have been no clinical trials assessing the combination of hyperthermia with immunotherapy. The study of hyperthermia with immunotherapy is particularly compelling when considered in the context of a new treatment paradigm for this anti-neoplastic modality. Novel concepts include ease of treatment including elicitation of the tumor-specific response of not requiring whole tumor heating, potentially shorter treatment time, better treatment tolerance as opposed to other multi-agent approaches to
immunotherapy and the ability to apply heat repeatedly with immunotherapies, unlike ionizing radiation. Several questions remained with regard to clinical integration which can be readily addressed with thoughtful clinical trial design building upon lessons learned at the bench and from clinical trials combining radiation and immunotherapy. Examples of promising avenues for clinical investigation of hyperthermia and immunotherapy including melanoma, bladder, and head and neck cancers are reviewed. In summary, there is a present convergence of factors in oncology that compel further investigation of the integration of hyperthermia with immunotherapy for the benefit of cancer patients.
The ability of hyperthermia to augment radiation therapy and chemotherapy has been demonstrated in clinical oncology as evidenced in many phases II and III trials [1,2] While not yet assessed in clinical studies as is the case with radiation or chemotherapy, pre-clinical work strongly supports clinical investigation of hyperthermia in combination with immunotherapy. Hyperthermia stimulates a broad array of anti-neoplastic immune responses across the clinical therapeutic temperature range as demonstrated in numerous preclinical studies. Notably, hyperthermia has been shown in vitro, and in some cases, in vivo to favorably multiple steps of the cancer-immunity cycle . These diverse mechanisms of action provide for a wide range of potential strategies to effect improved clinical outcome by way of the addition of hyperthermia to immunotherapy. While questions remain as to how best to integrate hyperthermia with immunotherapy, new thinking as to the application of hyperthermia in this setting provides a great opportunity to expand the use of both immunotherapy and hyperthermia to the benefit of cancer patients.
Hyperthermia – multifactorial immune effects
The effects of hyperthermia on the immune system are truly
multifactorial as demonstrated in vitro and in some instances,
in vivo. Hyperthermia results in both active and passive
release of tumor antigens. At temperatures of 41–43 C as
commonly used in the clinic, HSP and tumor-specific cancer
antigens can be released from intact cells in exosomes.
Direct release of HSP and tumor antigen spillage can occur
at these and higher temperatures [4,5]. Increased release of
HSPs into the extracellular environment stimulates downstream
immune activity and increases antigen presentation
[6–8], thus promoting the beginning of the cancer immunity
cycle. Once antigen uptake occurs, thermal stress facilitates
the migration of antigen-presenting cells (APCs) to lymph
nodes in part through up-regulation of MHC-I, MHC-II, and
several co-stimulatory molecules (e.g., CD80, CD86, CD40) on
APCs  with subsequent activation of T cells .
Furthermore, hyperthermia has been shown to enhance
immune surveillance by T-cells  and also up-regulates the
expression of toll-like receptor 4 (TLR4) on APCs, such as
dendritic cells (DCs), and induces the release of cytokines,
chemokines and nitric oxide which facilitate the induction of
adaptive immune response . The adaptive immune
response includes some of the players of the innate counterpart,
including T cells and APCs, and is equally heat sensitive.
Heat, in addition, enhances T cell trafficking to tumor by controlling
the persistence of lymphocytes by increasing the
depletion of c-FLIP (a master anti-apoptotic regulator) 
and inducing the expression of intercellular adhesion molecule
1 (ICAM-1) on high endothelial venules  which facilitate
the trafficking of T cells to peripheral tissue. Hyperthermia
also increases blood perfusion and decreases interstitial pressure
in tumors, which may facilitate the infiltration of therapeutic
co-stimulatory molecules or immune effector cells into
tumors [14,15]. Migratory and cytolytic activity of NK  is
also enhanced by hyperthermia by inducing the NKG2D clustering
which recognizes MICA (MHC class I polypeptide related
sequence A) on the tumor cell surface . Finally, apoptosis
of tumor cells results in part through thermal stress-induced
up-regulation of Fas ligand (FasL) and cytokines in effector T
cells . Given hyperthermia can stimulate the immune system
including tumor-specific responses, the addition of hyperthermia
to immunotherapy is likely to augment clinical
benefits obtained with immunotherapy alone.
Augmenting immunotherapy – a new paradigm for
The use of temperature for anti-neoplastic immune manipulation
presents a distinctly new paradigm for the application
of hyperthermia. The approach here proposed differs from
the use of hyperthermia with radiation or chemotherapy in
several key ways. Hyperthermia also has several advantages
when compared to the use of radiation with immunotherapy
that should facilitate clinical integration and expanded use of
both immunotherapy and hyperthermia. Central concepts of
this new paradigm include the lack of need to heat the
entire tumor with the goal of eliciting tumor-specific
responses, shorter treatment times, protracted repeated use,
a favorable toxicity profile and potential for multifactorial
Partial tumor treatment
The use of hyperthermia to augment immunotherapy introduces
a new paradigm for the application of heat in the
therapeutic setting which addresses past barriers to its more
widespread use. Hyperthermia has been primarily used to
enhance radiation or chemotherapeutic effects. Numerous
phase II and III trials have demonstrated the efficacy of
hyperthermia when added to radiation or chemotherapy
[1,2] yet hyperthermia remains an underutilized therapeutic
modality in oncology. While utilization has increased in
recent years, much of the resistance to use has been due to
challenges in adequately heating the entire tumor as is
required when combined with radiation therapy. Many studies
have shown temperature achieved in all (Tmin) or at least
90% of temperature sensors (T90) equate with better clinical
outcomes [17–19]. The use of hyperthermia to augment
immunotherapy represents an important new paradigm for
the application of hyperthermia that may significantly lower
the bar for successful treatment. Stimulation of both tumorspecific
and broad immune response with hyperthermia, may
not require the entirety of the tumor be heated. It may be
possible to stimulate a tumor-specific immune response by
merely heating a portion of a malignant tumor which
addresses one of the key challenges to the application of
hyperthermia to enhance radiation or chemotherapy.
Reduced treatment time
While widespread practice calls for applying hyperthermia for
one hour, it may be possible that significantly shorter treatment
times are required to elicit desired immune responses.
Simultaneous treatment, not routinely possible with radiation,
may also be feasible. Given these considerations, should clinical
hyperthermia be established as an effective immunotherapeutic
agent, widespread adoption could be easily achieved
for many tumors such as melanoma, head and neck and bladder
cancer. Shorter treatment times combined with focal heating
should facilitate patient convenience and acceptance.
Protracted repeated use
Current NCCN guidelines call for the use of checkpoint inhibitors
including anti-PD-1 and anti-CTLA 4 therapy as first-line
treatment of several malignancies such as metastatic melanoma
and lung cancer. Patients responding to treatment
receive an extended course of therapy, typically receiving
treatment every 2–3 weeks over a period which frequently
extends months or even years. Importantly, there are no limitations
to repeated use of hyperthermia as opposed to ionizing
radiation. Use of ionizing radiation is limited due to
cumulative effects on normal tissues. Typically a short course
of radiation is administered with a single cycle of immunotherapy
after which responders continue treatment with
immunotherapy alone. However, hyperthermia could be used
routinely with each cycle of extended courses of anti-PD-1
therapy, anti-CTLA 4 or other immunotherapies as per standard
practice, should benefit be established.
Favorable toxicity profile
Notably, hyperthermia is associated with only minimal toxicity
as noted in dozens of clinical trials . From the standpoint
of toxicity, the combination of anti-PD-1 therapy with
hyperthermia may be an attractive alternative to combined
anti-PD-1 and anti-CTLA-4 therapy. While this combination
therapy has been shown to improve relapse-free survival
compared to either agent alone, this clinical benefit comes
at the expense of grade 3 or 4 toxicity in approximately half
of the patients, thereby limiting its use [20,21].
Multi-factorial immune effects
Hyperthermia has been shown to impact on multiple phases
of cancer immunity cycle  as opposed to radiation for
INTERNATIONAL JOURNAL OF HYPERTHERMIA 5
which therapeutic strategies largely have been focused on
individual steps. For instance, most of the focus with the use
of radiation to stimulate immune response has been on
tumor cell damage or death leading to tumor-specific antigen
spillage with the development of an ‘in situ’ vaccine.
Hyperthermia may similarly stimulate such response but
may, for example, simultaneously stimulate NK cell activity
and ICAM-1 up-regulation facilitating trafficking of t-cells
primed for tumor destruction into the tumor micro-environment.
It is noted that many of these concepts remain to be
validated in vivo let alone in the clinical setting. This remains
a challenge to be addressed as the application of hyperthermia
with immunotherapy begins to be explored more
broadly in actual therapeutic scenarios.
Questions to be addressed
There are several questions to be addressed in contemplating
the addition of hyperthermia to immunotherapy. These
questions include, sequencing with immunotherapy, specifics
of timing, optimal thermal dose parameters for elicitation of
specific immune responses, and identification of markers
both prospective and post-treatment of response.
Importantly, these questions can be readily addressed and
answered building upon pre-clinical studies and clinical
experience with hyperthermia and radiation with the effort
put forth to date.
A basic principle to the administration of two or more
cancer therapies is how to combine them maximizing safety
and efficacy. From a safety standpoint, clinical experience
with combined radiation and immunotherapy is likely applicable
to a combination of heat and immunotherapy. Given
the widespread use of immunotherapy, the issue of use with
radiation arose early on in clinical integration. Published literature
supports widespread clinical experience indicating
that radiation and various regulatory approved immunotherapeutic
agents can be safely combined . The questions of
sequencing and timing of radiation and immunotherapy to
elicit optimal response have been more complex [23,24]. This
question has been made more challenging by the limitations
on the use of ionizing radiation. The ability to apply heat in
varied timing to immunotherapy on an individual patient
basis should facilitate treatment optimization. In the case of
in situ vaccine strategy concerns with the destruction of
immune cells critical for response by radiation whether in
the tumor microenvironment or in lymph nodes should be
of far less concern with hyperthermia, perhaps making timing
less of an issue.
Thermal dose parameters – dependent on both temperature
and time – equating with specific immune responses
remain to be defined. Preclinical studies have demonstrated
significant variations in how specific responses are elicited or
augmented with heat. For instance, higher temperatures
applied over a brief period may be best to augment CPI
therapy  while trafficking of T cells to tumor may benefit
from mild hyperthermia applied over a longer period of time
. Therefore, temperature gradients across a heated tumor
may be helpful in eliciting wide ranging immunotherapeutic
responses due to different dose profiles being associated
with differing immune effects.
In recent years, there has been rapid clinical integration
of genomic and mutational profiling to facilitate higher yield
treatment selection. For instance, microsatellite or mismatched
repair deficient (MMR) status now has a central role
in selecting therapy for colorectal cancer. For patients with
microsatellite unstable disease (MSI) or MMR deficiency,
immunotherapy is the standard of care while for patients
with microsatellite stable (MSS) disease, chemotherapy is
standard . In the case of CPI therapy, the role of PD-L1
expression as a marker for the effectiveness of hyperthermia
will need to be defined. Lastly, genomic profiling may be
useful in predicting which patients may benefit from hyperthermia
in combination with immunotherapy in a similar way
to a selection of radiation for the treatment of prostate cancer
Promising areas for clinical investigation
Hyperthermia has the potential to enhance immunotherapy
across a wide clinical spectrum. Promising avenues for initial
clinical investigation include but are not limited to melanoma,
bladder and head and neck cancers.
Clinical experience with hyperthermia to date
Melanoma is a disease for which benefit of hyperthermia has
been established in a phase III trial as reported by Overgaard
et al. In this multicenter trial, either 800 or 900 cGy for three
fractions was administered locally to melanotic lesions with
or without hyperthermia. Addition of hyperthermia was associated
with significantly improved complete response rate of
46 vs. 29% with radiation alone with complete systemic and
local control associated with improved survival with longterm
follow-up . While the investigation of application of
hyperthermia alone with immunotherapy is of its own merit,
it is interesting to note that the 8003 regiment used in
this trial has been found in a subsequent pre-clinical study in
a mouse mammary tumor 1model to be the optimal radiation
regimen to elicit abscopal responses . This convergence
of anti-tumor effects with this radiation regimen also
used in the phase III melanoma trial raises intriguing questions
as to how immunotherapy can be combined not only
with hyperthermia but potentially in combination with both
radiation and hyperthermia.
Clinical opportunities with immunotherapy
Melanoma has been the initial focus for the introduction of
several classes of immunotherapeutics into the clinic. As a
result, significant strides have been made in the treatment of
melanoma with immunotherapy, yet there remains an acute
clinical need for better outcomes. The first indication for a
checkpoint inhibitor (CPI) was established in 2010 for the
treatment of melanoma with ipilimumab, an anti-CLTA 4
agent . Randomized clinical trials have subsequently
revealed a survival advantage with anti-PD-1 agents such as
pembrolizumab and nivolumab as compared with the anti-
CTLA-4 agent ipilimumab or chemotherapy [32–35]. Despite
this progress, unfortunately only 30–40% experience any
objective response and the median time to progression for
those who do respond is between 5 and 7 months [32–35].
Complete response rates are considerably lower, generally in
the range of 10–15%. Combined anti-PD-1 and anti-CTLA-4
therapy have yielded higher response rates in the range of
60% but at the cost of over half of patients experiencing
grade 3 or 4 toxicity [20,21]. Due to the considerable toxicity
of this treatment approach, a majority of the patients may
not be suitable candidates for combined therapy due to age
or comorbidities. In this large group of patients, single-agent
anti-PD-1 therapy continues to be the preferred standard of
care first-line option, despite the lower response rates.
Therefore there remains a compelling need for therapeutic
strategies to enhance existing immunotherapies for melanoma.
As primary melanomas and many metastatic lesions are
readily amenable to the use of superficial hyperthermia,
application of hyperthermia can be done with relative ease
and with repeated administration with each cycle of
Clinical experience with hyperthermia to date
Combined hyperthermia and chemotherapy has proven
beneficial in the treatment of non-muscle invasive bladder
cancer. In a multicenter trial, 83 patients with stage Ta
andT1, gradeG1 to G3 transitional cell carcinoma of the bladder
were randomized to receive mitomycin C with or without
radiation therapy following complete transurethral resection.
Patients with low-risk disease were excluded. Patient and
tumor characteristics were evenly matched. Freedom from
tumor recurrence, the primary endpoint was significantly
improved with the addition of hyperthermia to 83% as compared
to 42% with mitomycin C alone . In a subsequent
report of long-term results, this benefit was maintained with
median follow-up for tumor-free patients of 91 months. Tenyear
disease-free survival was 53% versus 15% with versus
without hyperthermia .
Clinical opportunities with immunotherapy
Immunotherapy has an established role in the treatment of
urothelial bladder cancer. Bacillis Calmette Geurin (BCG) was
approved by the FDA in 1990 for intravesical treatment of
superficial bladder cancer and remains the primary agent in
the treatment of early bladder cancer to this day. Checkpoint
inhibitor therapy is now part of the standard of care management
for locally advanced and metastatic bladder cancer
with an ongoing investigation of earlier use with chemotherapy
in advanced disease. Atezolizumab, an anti-PD-L1 agent,
was the first CPI approved by the FDA in bladder cancer for
the treatment of locally advanced or metastatic disease
refractory to platinum-based chemotherapy .
Atezolizumab administered every 3 weeks resulted in an
objective response rate of 16 and 28% with robust PD-l1
expressing tumor-infiltrating immune cells [39,40] with
respective 1 year overall survival of 37 and 50%, respectively.
Presently, the combination of atezolizumab with or without
gemcitabine and platinum-based chemotherapy is under
active investigation. Similarly, other CPIs including nivolumab,
pembrolizumab, avolumab and durvalumab are all in
various phases of investigation and regulatory approval for
treatment of bladder cancer. Other agents as, for instance,
indolamine 2,3-dioxygenase (IDO) inhibitors and tumor
necrosis factor receptor superfamily member 4 (OX40) targeted
drugs are also under active investigation.
While results with immunotherapy are encouraging similar
to melanoma, there is clearly an opportunity for improvement
for which hyperthermia holds promise. The combination
of immunotherapy and chemotherapy as assessed in
ongoing trials presents an intriguing opportunity for the
study of hyperthermia in combination with these two therapies.
Beyond the potential enhanced immune effects, hyperthermia
also enhances the effects of chemotherapy . In
particular, platinum-based agents have potential synergistic
interaction with hyperthermia noting these agents cause
DNA damage in tumor cells for which repair can be inhibited
by hyperthermia . Furthermore, in consideration of the
different mechanisms by which immunotherapeutic agents
now under study exert effects, hyperthermia may interact
favorably in taking advantage of these varied immunotherapeutic
Head and neck
Clinical experience with hyperthermia to date
With regard to head and neck cancers, two randomized trials
have revealed benefit with the addition of hyperthermia to
radiation [43,44]. In one study, pre-dating routine use of
chemotherapy in locally advanced head and neck cancer,
patients were randomized to radiation alone versus radiation
and hyperthermia. For patients with stage III or IV disease,
the complete response rate was increased from 20 and 7%
with radiation alone to 58 and 38%, respectively, with the
addition of hyperthermia . A phase III trial in Italy from
this era assessed the impact of hyperthermia when applied
with radiation in the treatment of N3 squamous cell cervical
lymph nodes. A planned interim analysis inclusive of 41
patients revealed a complete response rate in the combined
arm of 82% as compared to 37% with radiation alone. Longterm
analysis revealed 5-year overall survival of 55 versus 0%
in the hyperthermia versus radiation alone arms .
Clinical opportunities with immunotherapy
Similar to the other disease sites, immunotherapy now has
an established role in the management of advanced and
metastatic head and neck cancers, albeit with, at times, modest
benefits as compared to other diseases. Cetuximab is a
monoclonal antibody which targets the epidermal growth
factor receptor (EGFR). Addition of Cetuximab to radiation is
now standard treatment in locally advanced head and neck cancer and similarly standard treatment, which is approved
by the FDA for chemotherapy in recurrent or metastatic disease
[45,46]. CPI therapy has subsequently been incorporated
into the management of recurrent or metastatic disease.
Pembrolizumab, regardless of PD-L1 expression, received
accelerated approval by the FDA in 2016 following favorable
results from a phase 1 b trial . Overall response was 16%
with a complete response of 5%. A subsequent phase III trial
showed a 19% reduction in risk of death compared to
chemotherapy which fell just short of statistical significance
. A subsequent study of first-line use of pembrolizumab
compared with chemotherapy in recurrent or progressive disease
revealed improved overall survival with immunotherapy
. Similar results have been noted with nivolumab including
a phase III trial for patients with recurrent disease. This
study showed a response rate for nivolumab of 13% and significant
but clinically modest improvement in overall survival
from 5.1 to 7.5 months with nivolumab vs. chemotherapy or
cetuximab. Greater difference in one-year survival, however,
was noted with nivolumab: 36 vs. 17% . Current investigational
efforts are focusing on the combination of immunotherapy
with chemoradiation in the primary treatment of
locally advanced disease.
There are several clinical opportunities to be explored for
the combination of hyperthermia with immunotherapy in the
treatment of head and neck cancers. Noting the generally
modest response rates of CPIs for head and neck cancers as
compared with melanoma, hyperthermia may play an
important role in expanding efficacy and use in this patient
population. Similar to and expanding upon opportunities
with bladder cancer, a combination of hyperthermia not only
with chemotherapy and immunotherapy but also radiation
therapy may provide for multifactorial treatment enhancement
with the addition of heat. Hyperthermia might also
enhance monoclonal antibody expression for agents such as
cetuximab in head and neck cancer, herceptin in breast cancer,
and rituximab in non-Hodgkins lymphoma CD20. A collaborative
study between the National Cancer Institute and
Thomas Jefferson University found that radiation enhances
total and cell surface expression of these monoclonal antibodies
. Preliminary analysis of hyperthermia revealed
similar potential with increased tumor cell sensitivity to NK
cell-mediated killing and antibody-dependent cell-mediated
cytotoxicity with cetuximab.
Hyperthermia holds great potential to further the application
of diverse approaches to immunotherapy to the benefit of
cancer patients. Additional mechanistic and in vivo studies
will aid in the realization of promising strategies for combining
these two modalities. New paradigms applied to the
application of hyperthermia with immunotherapy stand to
address identified limitations to each of these modalities.
Compelling clinical indications including use in the treatment
of melanoma, bladder and head and neck cancers amongst
others await clinical study well deserving of a fraction of
resources dedicated to the study of other strategies for augmentation
No potential conflict of interest was reported by the author.
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