1. Carlson, Robert H.

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SAN ANTONIO-A potential synergy between radiotherapy and immunotherapy in the treatment of advanced melanoma was described here at the American Society for Radiation Oncology Annual Meeting.

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In the Phase II trial (Abstract 215), a combination of the systemic anti-CTLA-4 agent ipilimumab with local radiotherapy produced higher response rates than seen with ipilimumab alone.


The researchers, led by Susan Hiniker, MD, an instructor in the Department of Radiation Oncology at Stanford University School of Medicine, explained that although checkpoint inhibitors such as ipilimumab are an innovative and promising approach to cancer immunotherapy, they have yet to produce high rates of response on their own and have been associated with immune-related toxicities.


The trial, designed to investigate whether use of radiation could potentiate the immune response, included 22 patients with stage IV melanoma treated with palliative radiotherapy and intravenous ipilimumab (3 mg/kg) every three weeks, for a total of four treatment cycles. One or two metastatic sites were treated with radiotherapy within five days of the initial immunotherapy treatment, and all the patients had at least one non-irradiated metastatic site that was at least 1.5 cm for assessment of response.

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Speaking at a news conference highlighting "Novel Clinical Paradigms," Hiniker said the primary objective was safety, with tumor response a secondary assessment. Tumors were assessed at two to four weeks following the fourth cycle of ipilimumab, and then every three months until disease progression. Patients also had blood drawn during and after treatment for evidence of immune response to therapy.


Hiniker reported that 11 of the patients (50 percent) had an initial response to therapy, including complete and partial, as well as and stable disease, at a median follow-up of 38 weeks.


Three of those patients (14%) have an ongoing systemic complete response to the combination therapy at a median of 55 weeks follow-up; three patients (14%) had an initial partial response for a median of 40 weeks; and five patients (23%) initially had stable disease following treatment, without progression for a median of 39 weeks.


Eleven patients had progressive disease on the first post-treatment scan. Hiniker noted that these responses compare with the results in previous trials in metastatic melanoma, where ipilimumab alone produced response rates of five to percent, with durable responses and a few rare complete responses.


She noted that an earlier prospective study of 22 patients treated with ipilimumab and radiotherapy showed an overall response rate of 18 percent, with no significant added toxicity.


Hiniker said patients in this new trial showed no significant added toxicity from combination therapy, and no apparent exacerbation of either radiation or ipilimumab-associated toxicities: "That is meaningful, because ipilimumab on its own has a quite high rate of grade 3 to 4 toxicity-generally on the order of 20 percent."


She explained that ipilimumab blocks the CTLA-4 co-inhibitory receptor on T cells, blocking its interaction with B-7 on antigen-presenting cells, and therefore blocks an inhibitory signal on T cells, promoting the adaptive immune response. "Multiple trials have shown ipilimumab response rates of approximately 15 percent. The responses can be quite durable, but rarely are they complete responses."


Local irradiation can modulate the local tumor environment and promote immune responses in several ways, she continued-for example:


* Through the upregulation of pro-inflammatory cytokines such as MCP-1, MIG, and IP-10, and there may be a relationship between elevated CD8-activated T cells and response; and


* Tumor antigens and neoantigens may also be released, dendritic cells activated, and cross-presentation of tumor antigens enhanced.



Potential Biomarkers

The next step will be to determine which patients will respond to the combination treatment, Hiniker added, noting that there was an interesting correlation between responders and grade 2 and 3 hypophysitis, an autoimmune endocrinopathy in the pituitary. This may reflect a more effective immune response in those patients, she said.


"More important will be biomarkers, and we did find higher levels of IL-2 during pre-treatment and treatment, as well as higher levels of CD8 central memory T cells, in patients who had good response."


Future RT Studies with PD-1 Inhibitors

At the news conference, Hiniker was asked to comment on the fact that ipilimumab is reported to be replaced by PD-1 checkpoint inhibitors, which are more efficacious and less toxic: "Ipilimumab is sort of on its way out, although recent studies support the combination of a PD-1 checkpoint inhibitor plus ipilimumab," she said.


A multicenter Phase II trial is under consideration that would combine radiation with anti-PD-1 agents, which may or may not also include ipilimumab, Hiniker said.


"When we opened this trial [with ipilimumab] there was much less data on PD-1 inhibitors, but the next stop will involve PD-1 inhibitors plus radiation. There is not much information on that combination yet, but there is exciting preclinical data from the Penn group in mouse models that found non-redundant mechanisms."


'Remarkable Eradication'

The moderator of the news conference, Catherine Park, MD, Professor and Chair of the Department of Radiation Oncology at the University of California, San Francisco, said: "We don't see that type of remarkable eradication [as in the Stanford trial] with radiation therapy alone-I think the response is quite striking. And there will be more to come; this study only scratches the surface."