Wednesday, April 27, 2016

Tumor burden, not cancer per cell antigen density or T cell receptor affinity, determine immunotherapy outcome

The checkpoint inhibitors and adoptive T cell therapies, though quite expensive, are transforming cancer management and outcome. However, even in the best scenario, currently available immunotherapies against few solid tumors work in ~30% of cancer patients. By "work" clinician usually mean treatment when immunotherapy delays patient's death from cancer for  >1 year.

Right now, there is no specific marker that can reliably predict a success or a failure of cancer immunotherapy. So far, best evidence points to a density of cancer-associated mutations as a positive predictor of success in immunotherapy. However, it is too early to generalize this correlation.

For example, following paper published in Journal of Immunology highlights our incomplete understanding of cancer-immune system relationship. Here,  the authors showed that it was overall tumor burden [tumor mass + antigen] rather than cancer [per cell] antigen density or affinity of adoptively transferred T cells that determined outcome of immunotherapy.

For this study the authors used non-Hodgkin mouse lymphoma model, Eµ-myc, engineered to express different amount of OVA antigen. For adoptive T cells, OT-I (high affinity) and OT-3 (low affinity) CD8 T cells were used that differed in their TCR affinity to OVA.

First, the authors injected lymphoma cells and 2 days later transferred high and low affinity T cells. Surprisingly both T cells were able to eliminate lymphoma cells.

Next, the authors repeated the same experiment but this time they transferred T cells 5 days later. This time, both T cells failed to eliminate lymphoma cells.

Moreover, both T cell types exposed to day 5 lymphoma underwent functional "exhaustion" and failed to eliminate antigen-pulsed target cells.

In a separate experiments, the authors also used lymphoma cells expressing different amount of OVA. However, while OT-I could eliminate both types of lymphoma cells when transferred on day 2 post tumor inoculation, the same OT-I were impotent against lymphoma cells when transferred on day 3 post tumor inoculation.

Interestingly, whereas only OT-I CD8 T cells exposed to OVAhigh tumor cells down-regulated their TCR receptor, both type of tumors (OVAhigh and OVAlow) induced up-regulation of PD1 on OT-I cells.

In summary, this simple study suggests following: neither TCR affinity nor per cell density of mutated antigens determine immunotherapy outcome. Rather it is overall tumor burden [meaning, total level of cancer antigen + total tumor mass] could influence immunotherapy outcome. Another conclusion from this study, though not formally tested, is that co-administration of PD1 checkpoint inhibitors may benefit adoptive T cell therapy.

David Usharauli

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