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Yagawa et al. Cancer immunity and hyperthermia

(HECKEL HT3000, Heckel medizintechnik GmgH, flow. These perceptions indicate the synergetic effect
Esslingen, Germany), and have performed combination of combination use of radiotherapy and hyperthermia .
[7]
therapy with adoptive transfer of CD3-activated T-cells Moreover, additional use of DNA repair inhibitors was
and cancer-antigen loaded DC vaccines. Patients with reported to further enhance its efficacy [84] .
various solid tumors were vaccinated once a week
with DC vaccine prepared from autologous monocyte- Combination therapy with chemotherapy
derived DCs, which were pretreated with tumor antigens. Chemotherapy is the most popular therapeutic method
The DC vaccine was injected intradermally near the for patients with inoperative cancer and recurrent or
inguinal lymph nodes and CD3-activated T-cells were metastatic cancer; however, there are serious problems
administered intravenously [Figure 4A]. Some patients including its uncertain efficacy, drug resistance, and
underwent whole-body hyperthermia at the same time, adverse effects. To improve therapeutic results,
with the target rectal temperature set at 38.5 °C and combination use of hyperthermia was tested, and
heat-retention for another 1 h [Figure 4B and C]. To increased anticancer effect was reported in paclitaxel,
evaluate the induction of immune responses in patients docetaxel, gemcitabine, oxaliplatin, and irinotecan [85] .
who received antigen-loaded DC vaccination, we The mechanism of interaction of chemotherapy and
examined the onset of skin reaction at the vaccination hyperthermia was considered as follows: increased
site because this reaction indicates antigen-specific drug uptake into cancer cells by causing damage to
T-cell responses against tumor antigens presented the membrane of cancer cells and reducing oxygen
by DC vaccine. Then, we examined how much DC radical detoxification. Eventually, DNA damage
vaccination was required in each patient up to the increased while DNA repair decreased. Additionally,
point when delayed hypersensitivity like skin reaction hyperthermia was reported to have a potential ability
[86,87]
sizes 48 h after DC vaccination became consistently to avoid drug resistance . In addition, it is also
expected that elevated blood flow could result in a
larger than 1.5 cm in diameter. The average number of relative increase in anticancer drug concentration
vaccinations to induce skin reaction was 3.87 and 3.32 within the tumor. Moreover, adverse effects can be
in patients without and with whole-body hyperthermia, decreased because increased drainage of the drugs
respectively [Figure 5A]. Moreover, 12 of 19 patients may accelerate in normal cells due to the up-regulation
who underwent whole-body hyperthermia successfully of metabolism. On the other hand, some anticancer
elevated their core body temperature above 38.5 °C drugs, including 5-fluorouracil, gemcitabine, and
in every treatment and displayed earlier expression of oxaliplatin, are considered to enhance cancer immunity
skin reaction [Figure 5B]. This result indicated that the by inducing the infiltration of CTLs while reducing Tregs
combined use of hyperthermia with a DC vaccine and in the tumor [88] . Accordingly, enhancing the efficacy of
activated T-cells had a positive impact on the induction chemotherapy will result secondarily in up-regulation of
of T-cell based immune responses [76] . cancer immunity.

Combination therapy with radiotherapy Combination therapy with surgery
The enhancement of anticancer efficacy of combination Chemotherapy is usually performed for peritoneal
use of radiotherapy and hyperthermia was clinically metastases, but its prognosis is nonetheless bad,
recognized in cervical, breast, and head and neck because blood flow to the peritoneum is poor owing
cancer and so on [77] . Even though radiological to the presence of the peritoneal-plasma barrier [89] .
cytotoxicity induces DNA damage of cancer cells [78] , Hyperthermic effects are considered to impair the
some cancer cells can come back into existence peritoneal-plasma barrier and result in increased
(termed sublethal damage repair or lethal damage resorption of anticancer drugs in peritoneal tumors.
repair) [79,80] . In the analysis of the cell cycling, quiescent Hence, the combination of hyperthermia and
tumor cells were more resistant to irradiation because chemotherapy by intraperitoneal administration
cells in this stage have the potential for lethal damage resulted in more anticancer drug accumulation in
repair [81] . In contrast, hyperthermia can inhibit the repair peritoneal tumors than after chemotherapy alone [90] .
of radiation-induced damage in cancer cells, so that Using this concept, the effectiveness of cytoreductive
combination use of hyperthermia can enhance the surgery with subsequent HIPEC has been reported for
anticancer efficacy of radiotherapy [82,83] . Cells in the peritoneal metastasis from gastric [91] , colorectal [92,93] ,
synthesis (S) phase are also relatively radio-resistant, appendiceal [94] , and adrenal cancer [95] . Generally HIPEC
while they are the most sensitive to hyperthermia. is performed after resection of the cancer lesion with
Additionally, hypoxic cells in tumors are also radio- or without systemic peritonectomy by intraperitoneal
resistant, while hyperthermia improves the anaerobic administration of an anticancer drug containing saline,
condition by oxygen delivery due to increased blood which is heated in advance to maintain the peritoneal

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 225