Objective: Accumulating evidence exists for (1) an inverse correlation between the incidence of infectious diseases and cancer risk and (2) an inverse correlation between febrile infections and remissions of malignancies. This review is part of an effort of the Office of Alternative Medicine at the National Institutes of Health to examine this evidence. Methods: A review of the literature to a key word search was undertaken, using the following key words: fever, infectious diseases, neoplasm, cancer incidence and spontaneous remission. Results: The data reviewed in this article support earlier observations on the topic, i.e. that the occurrence of fever in childhood or adulthood may protect against the later onset of malignant disease and that spontaneous remissions are often preceded by feverish infections. Conclusion: Pyrogenic substances and the more recent use of whole-body hyperthermia to mimic the physiologic response to fever have successfully been administered in palliative and curative treatment protocols for metastatic cancer. Further research in this area is warranted.

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.

The prognosis of triple-negative breast cancer with metastases after chemotherapy remains dismal. We report the case of a 50-year-old female with first disease recurrence at the axillary lymph node and, later on, bilateral pulmonary metastases with severe shortness of breath. The patient received low-dose immune checkpoint blockade (concurrent nivolumab and ipilimumab) weekly over 3 weeks with regional hyperthermia 3 times a week, followed by systemic fever-range hyperthermia induced by interleukin-2 for 5 days. She went into complete remission of her pulmonary metastases with transient WHO I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of treatment, with recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases. This exceptional response should instigate further research efforts with this protocol, which consists only of approved drugs and treatments.

As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

Human peripheral blood mononuclear cells from healthy donors were treated ex vivo with the proteolytic enzyme bromelain and studied by flow cytometry. Bromelain-treated lymphocytes exhibited 60–90% reduced cell surface staining for CD44 and CD62-L molecules. While the staining for molecules CD 16, CD56 and CD49d was unaffected, a moderate increase (10–40%) in expression of the β2-integrins CD1 la-c was seen. This selective modulation of cell adhesion molecules (CAM) was seen on T cells and NK cells, as well. The selective modulation of CAM may help explain some of the clinical effects observed after bromelain treatment in patients suffering from chronic inflammatory disease, HIV and cancer.