The Discussion from the above article-
Cancer immunotherapy, which targets and modulates antitumor immune cells, differs mechanistically from cytotoxic therapies and kinase inhibitors, which directly mediate tumor cell death. Accordingly, these treatment approaches differ in their profiles of clinical activity as well as safety (22–24). The identification of factors predicting response to immunotherapy is highly desirable, to preselect patients most likely to benefit and spare others from unnecessary exposure to potential side effects. However, this is challenging due to the dynamic nature of the antitumor immune response and its heterogeneity across space (anatomic location) and time (progression from primary to metastatic cancer). We previously reported a correlation between pretreatment tumoral PD-L1 expression and response to anti–PD-1 therapy (nivolumab) in a subset of patients on an expanded phase I trial (16). In the current study, we have reexamined PD-L1 as a marker associated with anti–PD-1 response, and have extended our investigations to evaluate other factors in the tumor microenvironment potentially associated with the clinical activity of anti–PD-1.
Recent studies associate an inflammatory tumor microenvironment with responsiveness to certain forms of immunotherapy such as cancer vaccines and ipilimumab (25, 26), and our observations suggest that this may also be true for PD-1 pathway blockade. In the current study, patients whose tumors expressed PD-L1 were more likely to respond to anti–PD-1 therapy. Although PD-L1 is generally regarded as an immunosuppressive molecule, its expression is not necessarily synonymous with tumor immune evasion and may reflect an ongoing antitumor immune response that includes the production of IFNγ and other inflammatory factors (12). This is consistent with retrospective studies in select tumor types, such as melanoma, Merkel cell carcinoma, mismatch repair–proficient colorectal cancer, and NSCLC where tumor PD-L1 expression has been shown to be a positive prognostic factor (12, 13, 27, 28). We observed tumor cell surface PD-L1 expression in distinct patterns, which generally correlated with tumor type. Tumor cell surface PD-L1 expression was associated with immune cell infiltrates in some cases (mainly melanoma and RCC), whereas in others it was constitutive or out of proportion to infiltrating immune cells (NSCLC). We also observed instances of PD-L1 membranous expression on infiltrating immune cells but not on tumor cells, particularly in colorectal cancer (21). Although the biologic significance of these distinct expression patterns is currently unclear, they likely reflect the combined effects of innate and adaptive cellular and soluble factors that shape the tumor microenvironment, as well as the type of malignancy and composition of other components of the tumor stroma. For example, neoantigens associated with infection by tumor-promoting viruses or somatic mutational events in malignant cells may trigger inflammatory responses leading to local PD-L1 expression (13, 21, 27), while PD-L1 expression in non–virus-associated head and neck squamous cell cancers, glioblastoma multiforme, and anaplastic lymphoma kinase (ALK)–positive T-cell lymphomas has been associated with PTEN and ALK/STAT3 oncogenic signaling pathways (29–31).
In this study, we examined a potential relationship between TIL expression of PD-1, the direct target of nivolumab, with clinical outcomes but found only a borderline association. Because the intensity of immune cell infiltrates was significantly associated with tumor cell PD-L1 expression, we also explored the possibility that simply the presence of immune cell infiltrates might predict favorable clinical outcomes to anti–PD-1 therapy. The presence of TIL has been correlated with improved outcomes in retrospective studies of different tumor types, including melanoma and colorectal carcinoma (32–35). In addition, HER2-positive breast cancer patients with TIL in their pretreatment specimens have shown improved benefit from certain chemotherapeutic regimens (36). Further, increased numbers of TIL in posttreatment biopsies have been shown to correlate with the activity of ipilimumab in patients with melanoma (37). However, the current study is the first to examine the relationship of the presence of TIL in pretreatment tumor specimens to anti–PD-1 response, and a significant relationship between these factors was not observed. These findings suggest that the functional profile of TILs is a key factor determining PD-L1 expression (12). That is, TILs may be necessary to drive PD-L1 expression in some tumors, but their presence alone is not sufficient to induce PD-L1 and was not an independent factor correlating with clinical response in this relatively limited cohort. Because preclinical evidence suggests that anti–PD-1 can restore dampened B-cell functions (38), we also examined whether the presence and intensity of B-cell infiltrates correlated with clinical outcomes. Similar to our findings with CD3+ TILs, CD20+ B cells were significantly associated with PD-L1 expression by tumor and infiltrating immune cells, but their presence alone did not correlate with clinical outcomes following PD-1 blockade, suggesting the importance of defining cellular functional profiles. Other immune cell types, including suppressive cells (regulatory T cells and myeloid-derived suppressor cells), remain to be explored in the context of PD-1 pathway blockade (39, 40).
Recent work by others to analyze a potential association between pretreatment tumor PD-L1 expression and response to PD-1 pathway blockade—anti–PD-1 (41) or anti–PD-L1 (42)—has confirmed our original observation (16) linking PD-L1+ tumors with the likelihood of treatment response. However, in these new studies, some PD-L1–negative patients also responded to treatment, raising concerns that excluding the “marker negative” patient population from treatment might exclude potential responders. It is important to note that these three studies differ in the anti–PD-L1 mAbs used for IHC, staining techniques (manual versus automated), definitions of PD-L1 “positive” tumor (cell surface versus cytoplasmic expression, by tumor cells only or by other cells in the tumor milieu, threshold of “positivity”), scoring increments, and definitions of PD-L1 “positive” patients (based on a single tumor biopsy, or on maximal expression in the case of multiple biopsies from an individual patient). Also, because of the focal nature of PD-L1 expression within many tumors and emerging information about intratumoral genetic heterogeneity (43), if very small needle biopsies or dispersed single-cell cytology specimens are evaluated, a false-negative evaluation could potentially result. Another potential explanation for PD-L1(−) responders includes yet unidentified factors contributing to response. Despite these methodologic differences, the overall conclusions of these reports are remarkably similar, highlighting a robust association between the PD-L1 marker and mechanism-of-action for this class of drugs.
Although response rates are enhanced in the PD-L1+ patient population, it is currently unknown why the majority of PD-L1+ patients do not respond to PD-1 pathway blocking drugs. One possibility is that PD-L1+ tumors from nonresponders express additional dominant or codominant
immune checkpoints supporting treatment resistance. To address this, we examined PD-L2, the second known ligand for PD-1, for possible associations with PD-L1 expression and clinical outcomes. PD-L2 protein detected by IHC was found almost exclusively in geographic association with PD-L1 protein, consistent with its known upregulation by inflammatory cytokines, including IFNγ which also drives PD-L1 expression (44). However, PD-L2 expression was seen less frequently than PD-L1 in our series (in only 8 of 38 specimens examined), and no significant correlation with clinical outcomes was observed. Although the results of our series should be considered preliminary, similar conclusions were drawn in a recent report of PD-L2 expression detected by quantitative molecular techniques, in patients receiving anti–PD-L1 therapy (45). Studies aimed at identifying additional positive or negative predictive markers of response to anti–PD-1 treatment, and potential interactions among multiple factors in the tumor microenvironment, are currently under way in our laboratories.
In summary, this in-depth analysis of multiple factors in pretreatment tumor specimens from patients with advanced cancers receiving anti–PD-1 therapy prioritizes tumor cell PD-L1 expression as being most closely associated with objective tumor regression. It reveals other microenvironmental features, such as TIL PD-1 expression and the intensity of T-cell and B-cell infiltrates, as being associated with PD-L1 expression by tumor cells or immune-infiltrating cells, but not independently associated with treatment response. Thus, PD-L1 expression reflects an immune-active tumor milieu, and may illuminate additional tumor types that should be targeted for clinical testing with PD-1 pathway blockade. These results should still be considered preliminary, and ongoing phase II and III clinical trials of PD-1 pathway blockade are broadening the assessment PD-L1 expression as it relates to clinical outcomes including survival, in larger cohorts of patients. Additional investigations will be necessary to confirm these findings and will address whether multicomponent panels of pretreatment tumor markers may have more powerful associations with clinical outcomes, compared with individual factors. Assessment of on-treatment alterations in tumor molecular profiles will also be necessary to reveal whether tumors lacking PD-L1 expression and TILs may convert to PD-L1–expressing tumors following “priming” with combinatorial treatment regimens designed to incite an immune response, followed by PD-1 pathway blockade to liberate antitumor immunity.
. Since there is no way to definitively determine the status of her disease, she will continue on the Cediranib treatment as long as she is able to tolerate it, until she develops disease progression, or until a permanent ASPS treatment and cure is found. I don't have any more information about the status of Astra Zeneca's efforts to obtain pharmaceutical approval of Cediranib other than that which I shared in my update about the results of Brittany's most recent scans.