To start with, tumor-associated antigens (TAA) don’t clearly differentiate them from normal cells. Rather, they are just expressed a lot more by tumor cells compared to normal cells. That’s why tumor-associated, not tumor-specific. Identifying antigens that only tumor, and not normal, cells express at high levels is difficult and a major part of the problem in figuring out how to devise tumor-specific immunotherapies. Ideally such antigens would also be
- Crucial for tumor survival, else they’d simply mutate away from expressing them.
- Immunogenic, else the immune system wouldn’t target them.
Tumor antigens have generally been classified into 3 categories, TSA (Tumor-specific antigen) (), TAA and Cancer-germline or Cancer Testis Antigens (CTA) ( , ; see below from 3). and are typical examples of CTA.
NGS (Next Generation Sequencing,) shows
- Mutational landscape of human cancers is far more complex than previously envisaged ( ).
- Even different parts of the same tumor carry different mutations ( ) and higher intra-tumor neoantigen heterogeneity may be less sensitive to immune checkpoint blockade ( ). Such data suggest tumor-neoantigen-specific T cells are present in patients, that checkpoint inhibitors can lift their brakes to trigger effective tumor targeting, but that higher intra-tumor neoantigen heterogeneity may dilute anti-tumor T cell effectiveness, either by diluting antigen dosage or by reducing effectiveness. After all, if many neoantigens are expressed by a tumor, a given T cell would only effectively target some but not all of them.
Indeed this inherent heterogeneity is the bane of current targeted therapeutics, which aren’t personalized but rather stratified (see a below from). At the same time, TSAs being unique to each person, indeed to each tumor, forms the basis of active personalized cancer immunotherapy (see c below from ).
Inherent tumor heterogeneity presents a conundrum. Clearly, true promise oflies in harnessing the immunogenic potential of TSAs. Tumor neoantigens can indeed be targeted by the patient’s own immune system as recent studies have found ( , 9, 10).
However, relevant tumor neoantigens likely vary from patient to patient, relevant here meaning potential for being the target of effective immune response. Situation is far more complicated for T cell antigens since relevant ones aren’t simply those neoantigens that the tumor expresses but rather those that can make it through the stringent bottleneck ofand presentation to get presented to tumor-specific T cells by or . The patient’s HLA ( ) haplotype will thus also be a crucial parameter.
Such considerations imply personalized approaches rather than ‘off-the-shelf’ products will likely yield the most effective cancer immunotherapy. A conundrum because individualized Rx approaches present a challenge for regulators (). How to mitigate risk? How to assess safety, toxicity? All the steps comprising the well trod path applied to ‘off-the-shelf’ products aren’t feasible. Figuring out how to mitigate risk and keep costs down enough to make such treatments practicable for many and not just the purview of the super-rich are the major stumbling blocks for future TSA-based personalized cancer immunotherapy.
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8. Brown, Scott D., et al. “Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.” Genome research 24.5 (2014): 743-750.
9. Tran, Eric, et al. “Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.” Science 344.6184 (2014): 641-645.
10. Linnemann, Carsten, et al. “High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma.” Nature medicine 21.1 (2015): 81-85.