• Michael Misialek, MD

Immunotherapy Advances and the Role of the Pathologist

Immunotherapy made major headlines at the recent annual meeting of the European Society for Medical Oncology (ESMO). Major breakthroughs in breast, colorectal and head and neck cancer were presented at ESMO18 and will reshape how cancer is treated.

Triple Negative Breast Cancer

The anti-PD-L1 drug atezolizumab in combination with the conventional chemotherapy drug nab-paclitaxelwas shown to extend survival up to 10 months in patients with triple negative breast cancer.The combined treatment also reduced the risk of death or cancer progression by up to 40 per cent.

Colorectal Cancer

Results from the CheckMate-142 trial reported the anti-PD1 drug nivolumab and low-dose ipilimumab (anti-CTLA-4) shrank tumors and had beneficial effects on survival in patients with microsatellite instability (MSI)-high metastatic colorectal cancer. This combination could become a new first line treatment in some patients with metastatic colorectal cancers

Head and Neck Cancer

Immunotherapy with the anti-PD1 drug pembrolizumab improved survival in patients with head and neck cancer that had recurred or metastasized, according to results from the KEYNOTE-048 study.

The Role of Pathologists

Cancer cells utilize PD-L1 to inactivate T cells and “cloak” themselves to the immune system. By blocking PD-L1 with antibodies, the tumor can be “unmasked” and the immune system unleased to attack the tumor.

Pathologists are integral to establishing PD-L1 status of tumors. By examining tumor cells for expression of PD-L1 through antibody tagged stains, pathologists can score the tumor. Often this is done in concert with stains for T cells to assess the inflammatory cell component around the tumor.

Intratumoral expression of PD-L1 can occur through activated oncogenes or as a result of an adaptive immune response through upregulation of interferon gamma. Innate activation may or may not be associated with an active immune response.

Expression of PD-L1 can be heterogeneous and temporal. In this example a tumor cell is initially not expressing PD-L1 and a biopsy at this time would show PD-L1 negative tumor cells. Following therapy to enhance a T-cell response, activated T-cells recognize a foreign antigen and produce interferon-gamma which upregulates the expression of PD-L1. A biopsy at this time would show PD-L1 positive cells.

There are different immunohistochemical assays associated with each of the approved therapies. Based on the assay, therapy and indication, the threshold for positivity of PD-L1 varies. For some indications, PD-L1 is assessed only on tumor cells, while for other indications tumor cells and immune cells are assessed. It is likely that for at least some future indications, PD-L1 expression may only be assessed in immune cells. There is reasonably good correlation between the various IHC assays but the SP142 assay uses an amplified detection system that significantly increases detection in immune cells.

While PD-L1 expression is predictive of response to PD-1/PD-L1 therapies, 10-20% of tumors lacking expression still show benefit from therapy. Other predictors of responsiveness include the mutational load of the tumor and the density of CD8+ T-cells associated with the tumor. The higher the mutational load, the more likely that one or more of the mutations resulted in the expression of an abnormal protein recognized as foreign by the patient’s immune system. The presence of CD8+ immune cells may be the result of the immune system recognizing a foreign protein produced by the tumor and the density of CD8+ cells have been predictive of response to PD-1 therapy in some studies.

The perfect biomarkers to predict response to immunotherapy is still evolving. Pathologists are at the forefront in this search. Stay tuned to Path Report for breaking news.

#immunotherapy #PDL1 #cancer #breastcancer #coloncancer #headandneckcancer

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