Mechanisms of Response and Resistance to Immunotherapy

Orlando, FL—Despite remarkable advance in the treatment of cancer through the use of immunotherapy, outcomes still vary, and, for some patients, these regimens provide only a short-term answer. In addition, for many patients treated with checkpoint inhibitors, toxicity can be an issue.

At the 2017 American Society of Clinical Oncology–Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium, Jennifer A. Wargo, MD, MMSc, Associate Professor, Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, underscored the need to identify which patients will benefit from treatment, as well as the proper timing, sequence, and combination of these strategies to optimize response.

“We are beginning to understand that response and resistance to immunotherapy depend on a number of different factors, including tumor genome and epigenome, tumor microenvironment, host immunity, and the overall environment or microbiome. Moreover, these factors are all tightly interrelated. Optimal monitoring and targeting of therapy resistance requires a global, integrated approach, and, ideally, should include on-treatment assessment of immune responses,” said Dr Wargo.

As Dr Wargo reported, there are “tremendous efforts underway” to identify better predictive biomarkers for immune checkpoint blockade, but many insights have already been gained in the setting of metastatic melanoma. Patients who derive long-term benefit from immune checkpoint inhibitors, for example, tend to have higher mutational burden. In addition, research from Antoni Ribas, MD, PhD, Professor, Medicine, Surgery and Molecular and Medical Pharmacology, University of California, Los Angeles, has shown that density and distribution of infiltrating T-cells can be predictive of response, but these approaches are not perfectly predictive, and the latter can be difficult to quantify.

Building on this work, Dr Wargo and colleagues used a 12-marker immunohistochemistry panel to examine immune signatures in patients receiving a PD-1 blockade. Although only a modest difference was shown between responders and nonresponders in pretreatment biopsies, tumor biopsies completed early in treatment revealed a “profound difference”; in nonresponders, tumors remained “bland,” but in responders, researchers observed immune infiltrate that was highly predictive of later response.

“Early on-treatment biopsy showed a highly significant, nonoverlapping difference between responders and non­responders. These initial data suggest that if we just give a dose or 2 of PD-1 and look at early on-treatment biopsy, we can tell with relative certainty who will become a responder or not,” said Dr Wargo. “We may actually have predictive biomarkers present; we’re just looking at the wrong time point. We need to be looking at early adaptive immune response on therapy instead of pretreatment.”

According to Dr Wargo, research is also beginning to yield insights into the effects of systemic immunity and the actual environment on response to immune checkpoint blockade.

“Investigators have shown that host immunity can shape immune response through a process of immunoediting, and recent work has highlighted that systemic immunity is required for effective immunotherapy. In addition, there’s growing appreciation of the role of the environmental response to immunotherapy as a whole,” she said.

There is also increased evidence supporting the role of the microbiome in response to checkpoint blockade.

“Preclinical models have shown that the microbiome can modulate responses to checkpoint blockade, and that modulation of the microbiome can enhance responses to therapy,” she reported.

Inspired by this work, Dr Wargo and colleagues collected oral and gut microbiome samples from >200 patients with metastatic melanoma, before and after they received systemic therapy. Although no differences in diversity of oral microbiome were shown, the researchers identified significantly higher diversity of bacteria in the gut microbiome in responders to anti–PD-1 immunotherapy. Moreover, compositional differences in the microbiome were observed. According to Dr Wargo, responders to PD-1 therapy had more Clostridia and Bacteroidia.

The researchers then explored the relationship between compositional differences in the gut microbiome and tumor microenvironment. After performing immunohistochemistry staining and analyzing the density of the immune infiltrates, Dr Wargo and colleagues identified specific bacteria that were linked to antitumor immune response. An abundance of Faecalibacterium in the gut was strongly associated with a high density of CD8+ T-cells in the tumor microenvironment.

These researchers are currently developing clinical trials to test whether modifications to the gut microbiome could enhance therapeutic responses to immune checkpoint blockade.

“My hunch is that the unfavorable gut microbiome is essentially creating chronic inflammation and an immunosuppressive phenotype, which is translating into the tumor,” said Dr Wargo.