Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution

Abstract

The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0–92.8%), at 9 months was 73.5% (95% CI, 66.2–81.7%), at 12 months was 66.5% (95% CI, 58.6–75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

Complete Remission of Vocal Cord Cancer Treated With Low-Dose Ipilimumab Plus Nivolumab Combined With Interleukin-2 and Hyperthermia

“…Importantly, Kleef's approach takes advantage of mechanisms proposed in several immune models, including the DAMP model that needs for signals triggered by damage/danger-associated molecular patterns, the coinhibition model which is based on the assumption that negative feedback mediated by coinhibitory signals generates peripheral tolerance, and the quorum model which proposes that the adaptive immune system uses an antigen-specific counting mechanism [13]. Since the Kleef-protocol [8] consists only of approved drugs and treatments, our hypothesis that autoimmune T cells induced by a safe low-dose ICI therapy in combination with external hyperthermia and internal hyperthermia (IL-2) are powerful therapeutic tools can be confirmed or refuted in controlled prospective clinical trials.…”

“…In the above context, it was a very significant progress that we demonstrated in 131 unselected stage IV cancer patients with 23 different cancer types who were treated with the Kleef-protocol [ 8 ], an objective response rate of 31.3%, progression-free survival of 10 months, and survival-probabilities of 66.5% at 12 months. The irAEs of World Health Organization (WHO) Toxicity Scale grade 3 and 4 were observed in only 8.4% of patients suggesting that the combined treatment is safer than the established protocols without compromising efficacy.…”

“…As a matter of fact, our stage IV patients had several negative pre-selection factors such as antibiotic use in 24%, low PD-1/PD-L1 expression, 35.1% of patients had liver metastasis, which is associated with a specifically bad prognosis, and only 35% of the patients had ECOG 0, while all the patients were heavily pretreated. Despite these facts, 15.3% of the patients achieved a complete response with 20.7 months median time until progression [ 8 ]. The presented case is one of them demonstrating the potential of this new combination therapy.…”

“…In January 2018, the patient received a combined immune therapy, the Kleef-protocol [ 8 ] including loco-regional radiofrequency (13.56 MHz) hyperthermia (Oncotherm EHY2000 device) and whole-body hyperthermia (Heckel HT3000 device, Heckel Medizintechnik GmbH, Esslingen, Germany), low-dose combined checkpoint inhibitors (ipilimumab plus nivolumab), and individually titrated IL-2. Ipilimumab and nivolumab were dosed with 0.3 and 0.5 mg/kg, respectively, weekly over three weeks.…”

Therapeutic Induction of Tertiary Lymphoid Structures in Cancer Through Stromal Remodeling

“…In addition, TLS/ICB combination therapies could contribute to more effective anti-tumor responses with lower ICB doses. In this context, a preliminary study of low dose Nivolumab and Ipilimumab combined with IL-2 and hyperthermia treatment shows similar overall response rates when compared to high dose ICB with significantly lower overall toxicity ( 119 ). This indicates an exciting possibility to lower ICB doses when used in combination with other immune stimulating reagents.…”