Just a handful of years ago, malignant melanoma was a diagnosis with few treatment options. Oncologists had no obvious roadmap for this perilous disease and were forced to explore beyond targeted therapies and chemotherapy.

Charged with building the roads to success, they turned to immunotherapy; the work has led to breakthrough treatments. Today, a stronger network of therapeutic pathways has emerged, with novel immunotherapies being key modalities in the oncologists’ armamentarium of treatments for melanoma and many other solid tumors.

Cedars-Sinai Cancer investigators are among the pioneers incorporating immunotherapy with other treatments for melanoma, aiming to not only tackle resistance and metastasis—two of the most challenging aspects of care—but to make treatments work better for all melanoma patients.

"Tumors that were once treated only with chemotherapy are now being treated with immunotherapy," said Omid Hamid, MD, co-director of the Cutaneous Malignancies Disease Research Group at Cedars-Sinai and director of Phase I and Experimental Therapeutics. "People who used to live six to eight months are now living six to eight years—and beyond."

Hamid and his colleagues at The Angeles Clinic and Research Institute, an affiliate of Cedars-Sinai Cancer, have been instrumental in rewriting the story for melanoma and, as a result, many other cancers. Before the advent of targeted therapies and immunotherapies, the five-year survival rate for metastatic melanoma hovered at around 5%.

"Historically, melanoma was not a popular field of oncology to enter," said Mark Faries, MD, surgical director of the Melanoma Program at Cedars-Sinai. "The treatments were harsh and difficult, and the success rate was low. It was an enormous area of unmet need, but that enabled scientists to take chances."

Hamid and his team were among the first to conduct clinical trials and present promising scientific findings for pembrolizumab, an immunotherapy that is now a first-line treatment for advanced melanoma. Their findings were published in 2013 in the New England Journal of Medicine. The drug is now approved by the U.S. Food and Drug Administration for 40 indications, including lung, bladder, triple-negative breast, colorectal, esophageal and cervical cancers.

"This is no longer only about melanoma. What we’ve learned from melanoma is changing how we treat all solid tumors," Hamid said. "We’ve known for hundreds of years that the immune system can fight cancer. Patients with infections such as measles or mumps sometimes had tumor regressions. Now, with modern immunotherapy, we’re harnessing that potential in a way that is targeted, durable and far less toxic."

With the advent of targeted therapies and immunotherapies, the five-year survival rate for metastatic melanoma leapt from 5% to 50%, a staggering statistic that continues to drive the critical search for even better treatments.

Hamid and his colleagues are continuing to boost success in treating melanoma with a broad set of strategies.

Their research shows the promise of combination therapies, touting immunotherapy as an effective tool before and after surgery and in concert with other treatments. In a recent publication in Nature Medicine, they found evidence supporting presurgical treatment with immunotherapy as a promising strategy for patients with specific biomarkers.

Another breakthrough: A study published in the Journal of Clinical Oncology showed that immunotherapy can successfully cross the blood-brain barrier—an important milestone in treating brain metastases, which unfortunately occur in many cases of metastatic melanoma.

Cancer mRNA vaccines represent another promising personalized option for treating many tumors, according to a recent study published in Nature Medicine. Analysis of early trial results showed the vaccines successfully “trained” patients’ immune systems and generated durable T-cell responses in 71% of patients. Some of those responses lasted up to 23 months.

Furthermore, the T-cells successfully infiltrated tumor cells, where they were shown to harness the patient’s immune system to raze the tumor. Recently, personalized vaccines are increasing the ability to prevent recurrence in high-risk melanoma after surgery.

"Through our clinical trials program, novel therapies—including personalized vaccines—are available for patients who need more options, with the hope of finding the next paradigm-shifting therapy," Hamid said.

Despite the promising developments in immunotherapy, not all melanomas respond. The reasons could lie within the tumor microenvironment (TME). The TME is a complex ecosystem of immune cells, blood vessels, host connective tissue cells and signaling molecules that shields the cancer from the immune system. In healthy tissue, immune cells recognize and fight off threats, but cancer can remodel the environment to suppress the immune response.

"It’s not just the tumor you're fighting," said Ze'ev Ronai, PhD, director of the Cedars-Sinai Translational Research Institute and scientific director of the Surgical Melanoma Research Program at Cedars-Sinai. "It’s the entire system around it."

Investigators are examining how to turn the tide within the TME to support the immune system, protect the body and eliminate the cancer.

Ronai is studying macrophages in the TME that can promote metastasis. His team identified a metabolic and signaling pathway that drives macrophages to shield tumors and promote the spread of cancer.

In preclinical models, investigators genetically modified macrophages to switch off the genes involved in the signaling pathway, which returned the white blood cells to an immune-supportive state. They also tested compounds to block the cells from being reprogrammed, preventing the cascade of signals triggering the immune system to protect the cancer instead of the healthy cells. This strategy reduced cancer spread while restoring healthy T-cell activity, making the tumor vulnerable to immunotherapy. When combined with immune checkpoint inhibitors, overall treatment response also improved.

Metabolic barriers in the TME also pose a challenge.

"Understanding metabolism is critical," Ronai said. "It’s the fuel that drives cancer cells. Initially, there was huge excitement about targeting metabolism, but we quickly realized that it is not so simple. If we block a pathway in cancer cells, we might do the same to immune cells. The challenge is finding metabolic pathways that shut down the tumor without harming the immune system."

Bin Zheng, PhD, director of Melanoma Research in the Department of Biomedical Sciences and the Debra Black Chair in Melanoma Research, is studying myeloid-derived suppressor cells (MDSCs); they act as “bodyguards” for the tumor. They create a barrier to T-cells so that even if immunotherapy effectively gears up the immune system, it still cannot strike the cancer.

Zheng is examining the potential of the Type 2 diabetes drug phenformin as a cancer-fighting agent. In a previous Zheng Laboratory study, the combination of phenformin and a targeted cancer drug showed promising preliminary results. Zheng found that phenformin targeted tumor cells as well as reduced the MDSCs, boosting the immune response.

"So often, patients on a targeted therapy initially have a great response, but after a while—even while still taking the drugs—the tumor returns. That’s the problem of drug resistance," Zheng said. "Our initial findings in the phenformin trials tell us that targeting two different pathways is better than one."

Experts hope these steps will rob cancer of the home-court advantage it creates for itself within the TME, allowing immunotherapies and targeted therapies to work for a larger percentage of patients.

Ronai and colleagues are also tackling the problems of resistance and metastasis with artificial intelligence and computational biology. The team has trained machine learning algorithms to analyze large datasets from melanoma patients and flag patterns that signal early resistance. Those telltale signs include genetic mutations that arise after initial treatment, changes in the TME and metabolic shifts that fuel tumor survival in the face of therapy.

"We are trying a new approach: tracking how patients respond in real time to see if we can predict resistance before it happens," Ronai said. "We’re also going backward in time, analyzing patient data to find an early-warning signal for resistance—something that was there before the tumor stopped responding."

By comparing tumors before, during and after treatment, investigators can identify resistance markers before patients show symptoms. Big data has the potential to enable earlier interventions, guide tailored therapies, extend the effectiveness of immunotherapy and reduce recurrence rates.

In addition to treatment pairings, another winning combination is playing an important role to advance melanoma management: clinical expertise and scientific commitment.

"We have built a model where high-volume patient care and groundbreaking academic research coexist, bringing significant benefits to the community while leading innovations in immunotherapy," Hamid said. "We’ve been early adopters and contributors, guiding Phase I trials that have now come to fruition and shown real benefits. We continue to push the boundaries of what’s possible in immunotherapy."