Management of adverse events, modulation of autoimmunity, modulating microbiome treatment to cure cancer.

ICI have revolutionized the treatment of many cancers but the price to pay is the development of IrAEs in a substantial number of patients. Interestingly, patients developing IrAEs could have a better chance of tumor response. Thus, it is crucial to continue ICI in those patients and to correctly manage these side effects. Partners 3, 4 and partner 5 have set up a network called Immunotox of physicians both in IGR and Paris-Saclay hospitals for managing these IrAEs. FHU CARE allows to develop and consolidate this network with the involvement of basic scientists. Recommendations of management are provided for each organ disease involved by IrAEs.

The proof of this concept has emerged from the simultaneous occurrence of lung cancer and scleroderma in patients with anti-Pol 3 antibodies due to the occurrence of a crossed immunity between mutated and wild-type Pol 3 (Joseph, Science 2014). This concept has been confirmed with the spectacular efficacy of ICI. We extend this concept:

  • Modulation of the autoimmune response induced by ICI to better control cancer. it has been shown that overexpression of TNF at the cancer side could impair the effect of ICI. With DITEP partner 4 we design new protocols of treatment combining ICI and TNFi or ICI and IL-1β or IL-6 inhibitors.
  • Development of very sensitive technics for detecting cancer cells in patients developing an AID. If autoimmunity may be a way of curing cancer, we look at the presence of very rare cancer cells in patients with AID.
  • Microbiota analyses could identify responders to ICI. Manipulation of the gut microbiome (i.e., fecal transplantation or microbial complementation) may increase its efficacy and safety in those who have the unfavourable microbiota. More specifically, maintaining a balance between immunogenic and tolerogenic gut ecosystems may be obtained by restoring eubiosis, either by transferring healthy microbiota (as already performed in severe colitis after ICI or in IBD (Wang, Nat Med. 2018) or by oral feeding with immunogenic (A. muciniphila, E. hirae, B. fragilis (rev. in Zitvogel L, Science 2018) or tolerogenic (F. prausnitzii, (Alameddine, Front Immunol. 2019) bacteria as well as specific diet interventions (prebiotics or metabolites) modulating distinct T cell subsets. Preclinical models and ongoing clinical trials at IGR and INRA pave the way to these novel therapeutic interventions.
  • IrAEs may be considered as an experimental model of AID. But frequently, the emerging AID does not fulfill all the characteristics of the classical AID. Thus, these IrAEs may give new clues on pathophysiology of AID/ID. ICI-induced sicca and SS partner 1, ICI-induced colitis and IBD partner 6, ICI-induced nephritis partner 8 are studied, with the help of pathology departments of FHU CARE partner 21 and partner 22.
  • Numerous works have shown involvement of ICI in HIV, HBV, HCV infections, in tuberculosis and other infections. ICI have been used in chronic infections in animal models. Like in cancers, this strategy could be limited by irAEs. Partner 3 and partner 18 study the effect of ICI in macaques’ models of SIV infection and in human PML, a deadly infection. The schemes of ICI administration are different compared with cancer, that may help to understand the occurrence of irAEs. In parallel, safety of ICI in HIV-infected patients with cancer is studied in collaboration with the ANRS partner 3 and partner 23.

Timetable, deliverables and other proposed indicators

  • D3.1.1: Connection of Immunotox with basic scientists D3.1.2: Recommendations of management for each organ disease involved by IrAEs.
  • D3.2.1: Design of a clinical trial in one human cancer with a combination of ICI and a biologic targeting inflammation (TNF, IL1 or IL6)
  • D3.2.2: Mechanism of anti-cancer action of a combination of ICI with a biologic targeting inflammation (TNF, IL1 or IL6)
  • D3.2.3: A new sensitive technique for detecting cancer cells in AID

  • D3.3.1: Proof of concept of modulation of microbiota for improving efficacy of ICI in animal models
  • D3.3.2: Design of a clinical trial in one human cancer to test the concept