Comparison of the effectiveness of integrative immunomodulatory treatments and conventional therapies on the survival of selected gastrointestinal cancer patients.

In the last decade, the use of immunomodulating treatments (IMT) at integrative oncology providers (IOP) increased. IMTs are used to modulate the tumor microenvironment, which might lead to increased response-to-treatment, and the indication of immune checkpoint inhibitors might also be widened. The efficacy and safety of IMTs in advanced/metastatic gastrointestinal cancers were compared with conventional chemo(radio)therapy (CT). 21 colorectal- (CRC), 14 pancreatic- (PC), 5 cholangiocellular- (CCC), 5 gastric- (GC) and 4 esophageal cancer (EC) patients received IMT. IMT and CT were compared in CRC and PC. CT was administered at an academic oncology center. After the initiation of IMT, a median survival of ~ 20 (CRC, PC and EC) and ~ 10 months (CCC and GC) was observed. Of the IMTs, locoregional modulated electro-hyperthermia had the most positive effect on overall survival (HR: 0.3055; P = 0.0260), while fever-inducing interleukin-2, and low-dose ipilimumab showed a positive tendency. IMT was superior to CT in PC (HR: 0.1974; P = 0.0013), while modest effect was detected in CRC (HR: 0.7797; P = 0.4710). When the whole study population was analyzed, IMTs showed minimal effect on patient survival, still CT had the greatest effect if introduced as early as possible (HR: 0.0624; P < 0.0001). The integrative IMTs in the presented form have mild impact on gastrointestinal cancer patients' survival, however, we observed its benefit in PC, which warrants further investigations.

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

We present a 44-year-old male patient, exposed to tobacco smoke and alcohol, with a locally advanced, multiple recurrent squamous cell carcinoma (SCC) of the vocal cord who had undergone resection four times. The patient rejected the mutilating surgery or radiation therapy due to the expected severe lifelong consequences. Instead, the patient opted for complex immunotherapy combining low doses of checkpoint inhibitors ipilimumab-nivolumab (0.3 and 0.5 mg/kg, respectively) with fever-inducing interleukin-2 (IL-2) and hyperthermia, which induced complete remission (CR). Restaging with MRI and laryngoscopy demonstrated lasting remission ongoing now for two years. The fact that this patient is free of any cancer-related signs or symptoms raises the possibility of a long-lasting remission even after the fourth recurrence of a locally advanced squamous cell vocal cord cancer by the induction of therapeutic fever combined with a safe low-dose ipilimumab plus nivolumab therapy to endorse T-cell function.

Exploiting autoimmunity unleashed by low-dose immune checkpoint blockade to treat advanced cancer.

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.

Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2.

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.

Site-Specific Immunomodulator: A Novel Treatment for Crohn's Disease.

We investigated the mechanism of action, safety, and efficacy of the Site-Specific Immunomodulator (SSI) QBECO, a novel immunotherapy for Crohn's disease (CD). Using human monocytic THP-1 cells, we demonstrate that SSI QBECO (derived from the common colon bacteria E. coli) activates macrophages to an M1 phenotype (associated with enhanced capacity to eliminate bacteria and activate innate immune responses). We assessed SSI QBECO in a compassionate use protocol of ten adult patients with active CD. Patients with moderate to severe clinical symptoms receiving conventional CD treatments and/or complementary therapies were included, except patients receiving anti-TNF medications. SSI QBECO was self-administered subcutaneously every second day, for a minimum of 2.5 months and a maximum of 11 months. All 10 patients reported improvement of symptoms while on the SSI QBECO treatment. Seven patients reported full resolution of clinical symptoms during a course of SSI QBECO of at least three months. Three patients have experienced ongoing sustained clinical remission after discontinuing all medications, including SSI treatment. The longest case of clinical remission is still ongoing (>4 years). No serious severe adverse clinical events were reported. Collectively, we conclude that treatment with the immunoactive SSI QBECO was well tolerated and effective for treatment of Crohn's disease in this case series.