Immune-checkpoint blockade and T-cell based adoptive cell therapy have recently shown durable clinical effects on the patients with various advanced cancers. However, response rates are around 10-30%. Thus, the identification of biomarkers to select appropriate patients and immunotherapies as well as the improvement of immunotherapy efficacy possibly through combination strategy (including converting non-responders to responders for the immune-checkpoint inhibitors) are needed.
Pretreatment immune status of tumor microenvironments varies among cancer patients, and it correlates with prognosis and responses to various cancer therapies including surgery, chemotherapy, radiation, and immunotherapies. The immune status may be defined by cancer cell’s genetic characteristics (e.g. immunogenic passenger mutations, immunosuppressive driver mutations), patients’ immune-reactivity (e.g. SNPs), and environmental factors (e.g. smoking, microbiota). Because the immune status is different among cancer types, subtypes and individual patients, appropriate immune-interventions may need to be applied for each patient.
For combined immunotherapies, the following immunological issues may be considered; 1) identification of appropriate tumor antigens expressed in cancer initiating cells, 2) in situ tumor destruction to induce immunogenic cancer cell death, 3) enhancement of antigen presenting cells’ function, 4) in vivo activation of anti-tumor T-cells, 5) Reversal of cancer-associated immunosuppression (cancer induced primary and anti-tumor T cell induced adaptive immune resistances).
We have been screening various chemical compounds and antibodies capable of improving immunological conditions in tumor microenvironments, and found that some of them are able to augment anti-tumor effects particularly in combination with PD-1/PD-L1 blockade through various mechanisms in in vitro human and in vivo murine tumor models. Altogether, personalized combination therapy based on the evaluation of patients’ immune status may be exploited for further improvement of current cancer immunotherapies.