Could Nodal RT Explain Failure of ICIs in Head and Neck Cancer?

Liam Davenport

January 10, 2023

Immune checkpoint inhibitors (ICIs) have shown impressive efficacy in many different cancer types, but not in head and neck cancer. But it may not be the case that these drugs are ineffective in this cancer type; instead, it may be that the immune responses they elicit are being blunted by another concurrent treatment: elective nodal irradiation (ENI).

A new analysis outlines how ENI appears to decrease systemic immune responses, leading to local, distant, and metastatic tumor growth in head and neck squamous cell carcinoma (HNSCC).

The research, published recently in the journal Nature Communications, suggests that ENI should be avoided in HNSCC, and that it may explain why trials of immunotherapy combined with radiation therapy in this form of cancer have, so far, failed.

"It's not that immunotherapy doesn't work in head and neck," senior author Sana D. Karam, MD, PhD, told Medscape Medical News. "What failed is the design of our trials."

"The tragedy is…most companies are fleeing away from head and neck," she said, adding: "We have to give our patients a chance, and I hope this study shines a light on why, potentially, these trials did not work."

"The point here is: less is more" when it comes to radiation therapy in HNSCC, said Karam, an associate professor at the University of Colorado Denver at Anschutz Medical Campus in Aurora.

In the article, Karin and colleagues describe a murine (mouse) model of HNSCC, in which they targeted radiation to either the tumor only or to the tumor and also the bilateral lymph nodes (ie, nodal irradiation), and both sets of animals also received immunotherapy.  

The results were clear-cut.

ENI ablated the immune response to combined radiation and immunotherapy, and this was not seen in the animals who received radiation directed only at the tumor.

Specifically, ENI decreased antigen-experience T-cell expansion in the draining lymph nodes (DLNs) and infiltration into the tumor microenvironment, prevented T-cell activation, and promoted local, distant, and metastatic tumor growth.

This latter finding, Karam said, left her "shocked."

The team also turned to data from a clinical trial, which showed that, in humans, avoiding ENI generated a robust immune response, with activated T cells in non-irradiated lymph nodes.

Approached for comment, Randall Kimple, MD, PhD, said the study is a "wonderful example of how basic research studies can help shed light on the design of future clinical trials, and even potentially explain the results of trials that are not as successful as we initially hoped they would be."

Speaking to Medscape Medical News, he added that the results are "fascinating", and suggest that "radiation targeting only the tumor, when given in combination with immunotherapy, can stimulate a robust immune response that decreases the risk of cancer recurrence or metastatic spread."

Kimple, an associate professor in the Department of Human Oncology at the University of Wisconsin-Madison, agreed with Karam that the findings also imply that the negative results from the HNSCC immunotherapy trials may be "explained by the use of standard radiation treatments which block a robust immune response."

Also approached for comment, Nadeem Riaz, MD, MSc, a radiation oncologist at Memorial Sloan Kettering Cancer Center, in New York City, said these are "important data" and that, while the human data is "less strong" the results in the mouse model are "relatively robust."

The lymph nodes are "an important place were T cells are primed," he explained, and  irradiating the lymphatic region, alongside potentially killing cancer cells, is "dampening this priming effect."

As immunotherapy "works by activating the immune system," the question then becomes: "Now that we have this new pillar of cancer treatment, how do we combine all of these forms of treatment together in the most productive manner?"

"And so this study is opening up some questions about how we treat the lymphatics" to prevent locoregional spread "in relation to giving immunotherapy," he commented.

Multimodal Treatment Approach

The treatment of HNSCC typically involves radiation therapy, chemotherapy, and surgery, the researchers note, with therapeutic neck dissection and/or ENI used to minimize local and regional occurrence.

Yet, despite this "aggressive treatment regimen," approximately 50% of high-risk patients will have local, regional, or distant recurrence within 3 years.

There had been hope that adding immunotherapy would improve these outcomes.

However, even in the setting of recurrent or metastatic disease, the benefit from adding immune checkpoint inhibitors has been "non-existent or modest at best," the authors point out. "Why this is the case for a tumor subtype with relatively high tumor mutational burden, and moderate infiltration of immune cells in the tumor microenvironment, remains an enigma for the field."

They suggest that improving the response to immunotherapy requires a re-evaluation of how it is integrated into standard-of-care treatment, and focused specifically on ENI, because it could affect immune cell priming; moreover, the authors write, it is "often challenging for clinicians to evaluate the extent of nodal disease involvement."

The team set out to explore this question initially in mice with implanted HNSCC. They developed a radiation protocol to specifically target only the primary tumor in one group, and to target both the tumor plus the bilateral neck in a second group. Both groups also received immunotherapy.

In animals with tumor-only irradiation, 71% of distant tumors (5 of 7) were eradicated vs 43% (3 of 7) of those in mice also given ENI. Further studies suggested that ENI mice had increased primary tumor growth following treatment, as well as metastatic spread to the lungs, which was not seen in the animals that received tumor-only irradiation.

Similar findings were seen when the researchers performed neck dissection.

The team also noted that, although ENI did not affect the percentages of circulating CD45 cells, CD8 T cells, CD4 T cells, or NK cells, there were differences in the activation of these cell types between ENI and non-ENI mice.

Specifically, the investigators write, animals treated with ENI had a reduction in CD8 T cells expressing CD69, an early activation marker, and IL-2, a survival cytokine. Additionally, the researchers observed differences in CD4 T cells. They noted that CD4 T cells in ENI-treated mice had a reduction in Tbet, a transcription factor associated with a Th1 response, as well as in CCR7, a marker associated with homing to lymph nodes.

It was also observed that mice with reductions in CD8 and CD4 T cells were unable to eradicate their tumors, and that ENI appeared to dampen the immune response by decreasing the numbers of antigen-experienced T cells.

They also showed, however, that mice that eradicate local and distant tumors after tumor-only radiation often experienced regional recurrence, but that concurrent sentinel lymph node resection or sentinel lymph node irradiation was enough to reduce regional spread, while preserving the local and systemic immune response.

Finally, the team turned to data from a phase 1/1b clinical trial of neoadjuvant stereotactic body radiation plus durvalumab in patients with HPV-unrelated locally advanced oral cavity HNSCC.

These patients initially received tumor-only radiation, and then underwent ENI and neck dissection 3-6 weeks after the treatment had been concluded.

Comparing these patients with historical controls, and by examining non-irradiated lymph nodes, the researchers found that, by avoiding ENI, the non-irradiated lymph nodes showed activated T cells, unlike in nodes taken from nontreated individuals.

Even 3-6 weeks following treatment, lymph nodes that were routinely removed at time of surgery remained active and were "potentially priming tumor-specific T cells," the team says.

Overall, they concluded that "avoiding treatment with ENI in human patients with HNSCC induces a robust immune response…similar to what we observed in mice."

No funding was declared. Karam declares relationships with Genentech, Ionis, AstraZeneca, Roche. No other relevant financial relationships were declared.

Nature Communications. Published online November 16, 2022. Full text

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