| Paul Ehrlich famously coined the phrase "horror autotoxicus" in 1906 to describe the balance between self antigens and foreign. Unfortunately in cancer--T cells are often actively silenced or tolerized. You may be puzzled about the timeline. I too am often gobsmacked by the proprietary scramble to patent the latest biomarkers and checkpoint inhibitors as if the science was all new and shiny -- ripe for demanding astronomical drug costs. I was fortunate to attend the World Vaccine Congress 2017. The basic agenda reflected 7 co-located conferences all occurring simultaneously:
|  My interests are primarily Cancer & Immunotherapy. A strong background in genetics and oncology serve me well but the dynamic pace of R&D should humble anyone. The co-conference track as described " Cancer Vaccine Technologies and Adjuvants Delivery Systems, Vaccine Vectors and Antigen Discovery Technologies, checkpoint inhibitors" promised interactive discussions and shared data. On day one the plenaries were attended by the entire conference. I appreciated the level set across all of the different topics. |
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There is a lot to unpack regarding the latest science around immune-oncology and the dizzying pace of breakthrough approvals for checkpoint inhibitors and emerging science addressing personalized medicine. Basically, the outcomes have outpaced our understanding of the biology--but the forum of the World Vaccine Congress certainly softens the learning curve.
Jessica Fletcher, PhD from Genocea, a "vaccine company" shared an informative slide on the correlation of mutation profile to objective response rate (ORR), the proportion of patients with reduction in tumor burden of a predefined amount, to checkpoint blockade therapy. As depicted on the graphic below, mutation mismatch repair deficient (MMR-D) colorectal cancers (CRCs) have a more favorable stage-adjusted prognosis or outcome compared with MMR-proficient tumors (MMR-P). Not to over-simplify, but the more non-self an antigen, the more likely it is to elicit an immune response.
Jessica Fletcher, PhD from Genocea, a "vaccine company" shared an informative slide on the correlation of mutation profile to objective response rate (ORR), the proportion of patients with reduction in tumor burden of a predefined amount, to checkpoint blockade therapy. As depicted on the graphic below, mutation mismatch repair deficient (MMR-D) colorectal cancers (CRCs) have a more favorable stage-adjusted prognosis or outcome compared with MMR-proficient tumors (MMR-P). Not to over-simplify, but the more non-self an antigen, the more likely it is to elicit an immune response.
The Cancer Genome Atlas (TCGA) data portal contains harmonized cancer datasets within the National Cancer Institute Data Portal. This is an important resource for data projects within oncology reliant on genomic data. As a big believer in transparency and accessibility, I only share data sources that are either free or have minimal fees for access. I can answer specific questions on how to access this data or perform advanced search queries but what follows here are illustrative examples to highlight the complexity of mutational landscapes.
Mutational landscape and significance across 12 major cancer types
Somatic variants from 3,281 tumors across 12 tumor types from the TCGA Pan-Cancer analysis highlight "distributions of mutation frequencies, types and contexts across tumor types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects". What is important to observe is the sheer volume of mutations accumulated within human cancers with the majority being unique to individual patients. Below it is apparent that only a small percentage of these mutations are mutagenic.
It begs the question regarding broad epidemiological frameworks applied to genetically unique clinical outcomes. Outcome measures and clinical trial endpoint selection are hotly debated as they are inconsistently applied across immune-oncology trials. A convenient chart published in Oncology Endpoints in a Changing Landscape is an informative introduction to surrogate endpoints used in clinical research when overall survival isn't feasible.
There is much to learn, discuss, and discover in the evolution of our understanding of immune-oncology. Join the discussion or read along--stay-tuned...
Epidemiological, genetic and molecular biological studies have collectively provided us with a rich source of data that underpins our current understanding of the aetiology and molecular pathogenesis of cancer. But this perspective focuses on proximate mechanisms, and does not provide an adequate explanation for the prevalence of tumours and cancer in animal species or what seems to be the striking vulnerability of Homo sapiens. The central precept of Darwinian medicine is that vulnerability to cancer, and other major diseases, arises at least in part as a consequence of the 'design' limitations, compromises and trade-offs that characterize evolutionary processes.--Mel Greaves, Darwinian medicine: a case for cancer