CHICAGO—For decades, melanoma researchers reported one failed Phase III trial after another. All of that changed, however, with the development—and eventual FDA approval—of vemurafenib and ipilimumab. Suddenly, clinicians had treatment options to offer many of their patients, options that provide a reasonable chance of prolonged survival. The catch, though, is that in virtually all patients, the disease still progresses.
Therefore, investigators want to capitalize on the field's recent successes by combining the two approaches, immunotherapy and targeted therapy, and as reported here at the American Association for Cancer Research Annual Meeting, early data show that there is surprising biological rationale to think the approach might work.
“Traditionally we have had two silos: a signal transduction silo and an immunology silo,” said Patrick Hwu, MD, Chair and Professor in the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center and Associate Director of the Center for Cancer Immunology Research at The University of Texas Graduate School of Biomedical Sciences in Houston.
“We had different societies, different journals, no one knew each other. Melanoma is leading the way and bringing these two fields of science together, because we have both targeted agents and immunotherapy agents that are working—and we are showing there is an interplay.”
The Clinical Rationale
Hwu, along with numerous other speakers at the meeting, referred to the disparate progression-free survival curves associated with the new agents. Approximately 50% of patients treated with vemurafenib have a strong response, but the median duration of response is limited, with most patients having disease progression within six months to a year. By contrast, only a small percentage of patients treated with ipilimumab have a robust response, but those who do are likely to have prolonged progression-free survival.”
The principal question, then, is whether investigators can find a way to combine the agents and create a regimen that provides the best of both curves: a high response rate and durable responses. The critical answer will only come from clinical trials testing the combination, and one such study is already underway at numerous institutions.
BRAF Inhibitor May Boost Immune Response
In the meantime, however, several groups have been looking at the impact of BRAF inhibition on the immune system. They have found no ill effects, and some evidence of immune stimulation.
For example, Hwu's group reported that there were no adverse changes detected in 13 patients whose serum cytokines and T cells counts were measured before and after 28 days of treatment with dabrafenib. (Dabrafenib, previously called GSK2118436, is an experimental BRAF inhibitor similar to vemurafenib.)
Moreover, they saw increased T cell responses specific for tumor antigens in four patients tested. “We have to study more patients, but we are at least hopeful that in some cases we are going to see enhancement of tumor-specific immunity following these BRAF inhibitors,” he said at a plenary session at the meeting.
Furthermore, Georgina Long, MD, PhD, Professor of Medicine University of Sydney and Medical Oncologist at Westmead Hospital in Sydney, Australia, and colleagues found that vemurafenib treatment appears to help T cells infiltrate the tumor. “At baseline, if we look for CD4- or CD8-positive lymphocytes, there is no staining for those two lymphocyte subsets [in the tumor],” she said during a symposium devoted to melanoma therapy. “But early on in a responding lesion you get a nice strong infiltration for CD8-positive lymphocytes.” There was less change in the CD4-positive staining, she added.
Long also noted that researchers in Boston, led by Jennifer Wargo, MD, a surgical oncologist at Massachusetts General Hospital, and Keith Flaherty, MD, Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center, have seen similar changes in lymphocyte infiltration in patients following vemurafenib therapy.
Tumor-Immune Cell Interplay
To better understand how BRAF inhibitors alter immune responses, investigators have turned to mouse and cell culture models. Already several groups have identified immune-suppressing proteins that are secreted either by the tumor cells or tumor-associated fibroblasts, and most are in familiar pathways that drug developers are already working to block.
Noting that T cells often cluster around a tumor, with a layer of tumor-associated fibroblasts sandwiched between, Hwu's team suspected that the cancer cells were suppressing immune cell activity. Working in a cell culture system, they found that BRAF-mutant melanoma cells secreted something that inhibits T cells.
With further analysis they discovered that the BRAF-mutant melanoma cells produce interleukin 1 (IL-1), which then induces neighboring fibroblasts to produce immune-suppressing factors, such as COX-2, PD-L1, and PD-L2. Remarkably, if the researchers treat the melanoma cells with a BRAF inhibitor or the immune cells with an anti-PD1 antibody—which are currently in clinical testing—they lift the immunosuppressive effect.
Hwu said that based on these data, he thinks clinical testing is warranted: “We feel that if we block mutant BRAF and combine it with an antibody that blocks PD1, it is almost a vertical pathway blockade. Therefore, we think this should be a potent combination in patients.” Such combination trials are in the works, but no details are available yet, he said.
Meanwhile, the Houston-based team and a team led by Antoni Ribas, MD, PhD, at UCLA's Jonsson Comprehensive Cancer Center each discovered that BRAF alters T cell trafficking in mice, similar to what has been seen in patient biopsies. Working with a BRAF-mutant tumor model that is only partially sensitive to vemurafenib, the California group found that treating mice with vemurafenib and adoptive T cell transfer, which is another form of immunotherapy being tested in clinical trials, significantly improved progression-free survival, compared with either therapy alone.
“I don't have time to tell you all the studies we've done to try to piece this together and figure out how it is working...but one thing that has become very interesting to us is this phenomenon of activation of lymphocytes directly by vemurafenib,” said Ribas, Professor of Hematology/Oncology at UCLA, during a presentation at the meeting.
For example, if the team looks at how many antigen-expressing cells are killed in culture by tumor-infiltrating lymphocytes, they see the percentage double from 20% to 40% with the addition of vemurafenib—“It is a direct effect of vemurafenib on the immune system,” he said.
Researchers have previously noticed that vemurafenib has a paradoxical effect on BRAF-wild type cells compared with BRAF-mutant tumor cells. Whereas the drug slows proliferation or induces death in the mutant cells by turning down the oncogenic pathway, it stimulates the wild-type pathway and promotes cell proliferation and activation—the reason some patients treated with vemurafenib develop squamous cell carcinomas.
“Therefore, the drug has differential effects on melanoma cells and lymphocytes,” Ribas said. “Lymphocytes are activated through the MAP kinase pathway activation. The science supports combination therapies to advance the treatment of patients with metastatic melanoma.”
Dissecting the system further, Hwu's group found that vemurafenib treatment led to a dramatic decline in VEGF expression in mouse models and that blocking VEGF directly improved T cell trafficking to tumors. He added that Flaherty saw similar declines in VEGF expression with vemurafenib therapy in patient samples.
“We don't understand why VEGF keeps T cells out of the tumor, but it seems to. So we have the potential for a number of—low-lying fruit, I think—for combinations of targeted therapies and immunotherapies.”
Looking forward, Hwu is optimistic. “We have had a taste of success, but it is not enough. I think by combining things in the right way we can get much more lasting effects. I think we really have a great chance of getting more of our patients on that 10-year survival curve, which is where they all want to be.”
Hwu is on the advisory board of Genesis Biopharma, a company trying to commercialize tumor-infiltrating lymphocytes. Long is on the advisory board for several companies and receives research support from Roche. Ribas is a consultant for Kite Pharma and has received honoraria from Amgen, Celgene, Genentech-Roche, GlaxoSmithKline, Millennium, Novartis, and Prometheus.