As part of the 2020 Immunotherapy Bridge virtual congress (December 2nd-3rd, Italy), the Great Debate session featured counterpoint views from leading experts on three clinical questions in immunotherapy today. The first of these was whether antitumoral vaccination is still a treatment option. The second topic debated whether anti-programmed death (PD)-1/PD-ligand (L)1 blockade should be the backbone for immunotherapy combination. Finally, the use of innovative study designs and surrogate endpoints was considered from both an academic and industry perspective. For each topic, two experts presented the argument and counter-argument in support of two different points of view. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. The views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.

AbstractBackgroundImmunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu.MethodsTen non-human primates (NHP) of advanced age (18–26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals.ResultsAll juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control animals.ConclusionsOur results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system activation or other serious side-effects in both aged and juvenile NHP cohorts. A significant shift in the composition of soluble oligomers towards smaller species might facilitate removal of toxic Aβ species from the brain.

As part of the 2021 Immunotherapy Bridge virtual congress (December 1-2, Naples, Italy), the Great Debate sessions featured experts who were assigned counter opposing views on four important questions in immunotherapy today. The first topic was whether oncolytic viruses or other specific immunomodulators were the more promising approach for intralesional therapy. The second was whether early surrogate endpoints, such as response rate or progression-free survival, correlate with long-term overall survival was considered. Thirdly, whether vaccines can transform cold into hot tumors was discussed and, finally, broad versus deep analytic profiling approaches to gain insights into immune-oncology development were compared. As with previous Bridge congresses, presenters were invited by the meeting Chairs and positions taken during the debates may not have reflected their respective personal view. In addition, the views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity - basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA - an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510-41. ©2017 AACR.