[Hyperthermia Enhances Antitumor Effects of Immune Checkpoint Inhibitors and Immune Cell Therapy].

Hyperthermia is known to enhance the effects of radiotherapy and chemotherapy. We have previously shown that hyperthermia also enhances the effects of molecular targeted therapy, immune cell therapy, and immune checkpoint inhibitors (ICI). Here, we present the recent clinical data and research results that suggest the mechanism of enhancement.

[Dendritic Cell Therapy with Neoantigens and Oncoantigens].

We treated 3,164 patients with advanced cancer with dendritic cell therapy between July 2005 and March 2020. The effective rate in patients treated with dendritic cell therapy more than 3 times was 19.0%.

[Enhancing Antitumor Effects Using Hyperthermia(Including Immune Checkpoint Inhibitor)].

Hyperthermia enhances the efficacies of radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy. In this study, we investigated whether hyperthermia enhanced the efficacy of immune check point inhibitor therapy. The LLC tumor inoculated in mouse was heated and immunostained, which showed increase in PD-L1 staining post-heating.

[Effects of Immune Checkpoint Inhibitor Combined with Dendritic Cell Therapy and Hyperthermia].

In this study, 97cancer patients were treated with combined immune checkpoint inhibitor therapy and dendritic cell thera- py between June 2015 and April 2018. We administered nivolumab with 2-3mg/kg bw every 2-3weeks. The rate of progress in cases where nivolumab was administered more than 3 times was 55.

[Administration of Immune Checkpoint Inhibitor for Cancer except for Melanoma and Lung Cancer].

We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses.

[The effect of immunotherapy and hyperthermia on advanced or recurrent ovarian and uterine cancer - 229 clinical cases].

We treated 116 advanced or recurrent ovarian cancer and 102 uterine cancer patients with hyperthermia and/or immunotherapy(2005/7-2013/11). Of these, 63, 31, and 8 patients had cervical cancer, endometrial cancer, and uterine sarcoma, respectively. Standard therapy showed no effect or was refused by these patients.

[The effect of immunotherapy and hyperthermia for advanced or recurrent head and neck cancer - 74 clinical cases].

We treated 74 patients with advanced or recurrent head and neck cancer using hyperthermia and/or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. Fifteen(21.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent cancer - analyses by cancer type and recurrence form].

We treated 1,939 patients with advanced or recurrent cancer using hyperthermia and or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. There were 309(15.

[Immunotherapy and hyperthermia for the treatment of patients with advanced or recurrent colorectal cancer].

We treated 226 patients with advanced or recurrent colorectal cancer using hyperthermia or immunotherapy between July 2005 and September 2012. Clinical benefit (complete response [CR], partial response [PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients (13.3%), including CR in 5 patients.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent breast cancer].

We treated 172 patients with advanced or recurrent breast cancer using hyperthermia or immunotherapy between July 2005 and September 2012. In these patients, standard therapy showed no results, or it was refused. Clinical benefit( complete response [CR], partial response[PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients( 17.

[Immunotherapy with hyperthermia for advanced or recurrent breast cancer patients in whom standard therapy showed no effect or was refused].

We treated 168 advanced or recurrent breast cancer patients with hyperthermia or immunotherapy (2005/7-2011/12). In these cases, standard therapy showed no effect or was refused. Clinical benefit( complete response: CR, partial response, and long stable disease) was observed in 26 cases; CR occurred in 4 cases.

[Hyperthermic immunotherapy was effective in 3 CR cases as the standard treatments had no effects or could not be enforced].

We treated 1, 225 advanced or recurrent cancer patients with hyperthermia or immunotherapy (2005/7-2010/12). We had 174 (14.7%)clinical benefit cases (CR, PR and long SD) including 32 complete response (CR) cases.

[Hyperthemia enhances activated lymphocytes and molecular target therapy].

We already informed that a combination therapy of hyperthermia and activated lymphocytes therapy reduced the tumor growth and lung metastasis synergistically in mice model. In this study we treated mice inoculated LLC tumors with hyperthermia or molecular target drugs (erlotinib 25 mg/kg/day and sorafenib 10 mg/kg/day). Both of hyperthermia and molecular target therapy reduced not only tumor growth but also lung metastasis.

[Multidisciplinary therapy for 984 cancer patients--hyperthermic immunotherapy].

We treated 984 advanced or recurrent cancer patients with hyperthermia or immunotherapy (2005/7-2009/12). We have 137 clinical benefit cases (CR, PR and long SD) including 22 complete response (CR) cases. Effective rates of immunotherapy increased from 9.

[Mechanism of immunotherapy enhancement in cancer therapy by hyperthermia].

Although hyperthermia controls cancer alone, hyperthermia is more effective by using it together with chemotherapy and radiotherapy. In this study, we attempted to show that the effect of immunotherapy for cancer patients was remarkably enhanced by using hyperthermia.

[Hyperthermic immuno-cellular therapy-basic and clinical study].

BASIC: We treated mice inoculated LLC tumors with hyperthermia or activated lymphocytes. Both of hyperthermia and activated lymphocytes therapy reduced not only a tumor growth but also lung metastasis. And a combination therapy of hyperthermia and activated lymphocytes therapy reduced more of the tumor growth and lung metastasis synergistically.

[Effects of intratumoral injection therapy of dendritic cells combined with hyperthermia for cancer patients].

We proceeded with intratumoral injection therapy of dendritic cells (DC) in combination with hyperthermia for 41 cancer patients in the past two years. We confirmed a total of two CR cases (one of them already reported). We report two successful cases in this paper.

[Successful immunotherapy combined with hyperthermia therapy for cancer patients].

We proceeded with activated lymphocytes immunotherapy for 149 cancer patients, and hyperthermia therapy for 126 patients, and DC therapy for 20 patients in the past year. We were successful in two cases. Case 1: A metastatic pelvic cancer (unknown origin) patient treated with lymphocytes and hyperthermia therapy.

[Intratumoral injection of immature dendritic cells (DC) for cancer patients].

We proceeded with DC immunotherapy for 21 cancer patients. Immature dendric cells were injected intratumorally to the 16 patients, and three good and effective cases were obtained: case 1: A 69-year-old male patient with papilla-vater carcinoma, case 2: A 49-year-old female patient with gastric cancer, case 3: A 66-year-old male patient with malignant melanoma.