[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 55.2%. Dendritic cell therapy enhanced the immune checkpoint inhibitor therapy. In cases where the effect of combined immune checkpoint inhibitor therapy and dendritic cell therapy was restricted, hyperthermia and radiation therapy are useful for the recovery of combined therapy.

[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. PD-L1 and HLA class I staining increased after heating samples derived from a case of analinvasion of rectalcancer associated with Lynch syndrome.

[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(15.9%)patients who experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 52 CR cases. The effective rate of immunotherapy increased from 9.9%to 19.1%using hyperthermia. The effective rate for patients with hyperthermia-alone was 3.6%, and skin and regional lymph node metastases disappeared. Immunotherapy alone was effective for liver or lung metastases. Combined hyperthermia and immunotherapy had a beneficial effect on multiple metastases observed in important plural solid organs. Ovarian cancer had the highest effective rate (25.0%), followed by prostate cancer.

[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(21.4%) patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 4 CR cases. Hyperthermia alone was effective for one patient only. A combination of dendritic cell therapy and hyperthermia was beneficial for the remaining 14 patients. One patient was effectively treated with cetuximab, and γδ lymphocytes and dendritic cell therapy.

[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. Twenty-nine(25.0%)ovarian cancer patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months). The effective rate of a combination of therapies including activated lymphocyte therapy, dendritic cell therapy, and hyperthermia was 47.5%. Thirteen(12.7%)uterine cancer patients experienced a clinical benefit. The effective rates for cervical cancer, endometrial cancer, and uterine sarcoma were 7.9%, 22.5%, and 12.5%, respectively. Both hyperthermia and immunotherapy were administered to successfully treat these 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( 17.4%), including CR in 5 patients. The effective rate of immunotherapy increased from 7.7% to 26.0% using hyperthermia. The effective rate of hyperthermia was only 5.1%. The standard therapy had not been altered in 23 of the 30 patients in whom clinical benefit was observed. Thus, immunotherapy or hyperthermia had benefited these 23 patients. Of the 23 effectively treated patients, skin or regional lymph node metastases disappeared in 3 patients treated with hyperthermia alone, and lung metastases disappeared and carcinomatous pleuritis improved in 1 patient treated with immunotherapy alone. In the remaining 19 effectively treated patients, multiple metastases were observed in important solid organs such as the liver, lung, bone, and brain. Combined hyperthermia and immunotherapy was used to treat these 19 patients to good effect.

[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 effective rate of immunotherapy increased from 14.3% to 16.1% using hyperthermia. The effective rate of hyperthermia was 3.9%. Of the 30 effectively treated patients, liver metastases disappeared in 2 patients treated with hyperthermia alone, and lung metastases disappeared in 2 patients treated with immunotherapy alone. In the remaining 26 effectively treated patients, multiple metastases were observed in solid organs. Both hyperthermia and immunotherapy were administered and were found to be effective in the treatment of patients with advanced or recurrent colorectal cancer.

[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. The effective rate of immunotherapy increased from 9.1% to 23.9% using hyperthermia. Both hyperthermia and immunotherapy needed to be used together to be effective in 20 cases with distant metastases to solid organs.

[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. And a combination therapy of hyperthermia and molecular target therapy reduced more of the tumor growth and lung metastasis synergistically. The expression of HER2 and VEGFR was reduced by hyperthermia and molecular target drugs. Apoptosis was enhanced by hyperthermia and molecular target drugs synergistically.

[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. CASE 1: A 63-year-old male, rectal cancer, post operative recurrence with MRSA abscess located in abdomen. He was treated with dendritic cell therapy and hyperthermia. He showed a CR. CASE 2: A 62-year-old female, ovarian cancer, post operative recurrence. She was treated with standard chemotherapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR. CASE 3: A 46-year-old female, lung cancer, postoperative recurrence. She was treated with standard chemotherapy and molecular target therapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR.

[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 9.8% to 17.8% using hyperthermia. In the cases of ovarian cancer, head and neck cancer, lung cancer, prostatic cancer, gastric cancer, thyroid cancer and breast cancer, all confirmed high effective rates with hyperthermic immunotherapy.

[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. CLINICAL: We proceeded with hyperthermia (HT) for 472 cancer patients and activated lymphocytes (CAT) therapy for 384 patients and dendritic cell (DC) therapy for 94 patients. Two-hundred-thirty-eight patients of them underwent a combination therapy with hyperthermia and CAT therapy. And 92 patients received a combination therapy with hyperthermia and DC therapy. We proceeded with hyperthermia or immunotherapy for 526 cancer patients. And we have 67 clinical benefit cases including 8 complete response (CR) cases. These basic and clinical results indicate an effectiveness of a combination therapy with hyperthermia and cellular-immunotherapy for cancer patients.

[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. Case 1: A uterine cervical cancer patient with metastases in cervical and abdominal lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a CR not only in cervical but also in abdominal lymph nodes. Case 2: A sialyl grand cancer patient with metastases in cervical and axillary lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a PR.

[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. She showed a drastic response. Case 2: A metastatic lymph node cancer patient treated with DC, lymphocytes and hyperthermia therapy. She showed a CR.