An innovative treatment for one of the rarest cancers promises to be a Rosetta stone for more widespread forms.

The best thing you can say about uveal melanoma, a cancer of the eye, is that it is extremely rare — on the order of five cases per million. Otherwise, the news is not good. It resists treatment and likes to metastasize, a particularly bad combination.

Udai Kammula, MD, FACS, associate professor and director of the Solid Cell Therapy Program at UPMC Hillman Cancer Center, is working on a treatment for uveal melanoma. Through an innovative therapy called adoptive cell transfer, Dr. Kammula hopes to use the body’s own immune cells to fight the disease.

A blueprint for hard-to-treat cancers

This is good news not just for uveal melanoma patients, but for people fighting other more prevalent cancers, including pancreatic cancer, colon cancer, and liver cancer. “Uveal melanoma is a blueprint, a Rosetta stone, if you will,” says Dr. Kammula. “Because it is such a resistant tumor, understanding how to generate an effective immune response is, in my mind, the key to what’s happening in these other resistant cancers.”

Adoptive cell transfer focuses on a particular type of immune cell known as the tumor-infiltrating lymphocyte (TIL). It’s one of the body’s own cancer fighters. But it has barely a fighting chance against uveal melanoma and other resistant cancers. “The immune system doesn’t recognize cancer very well,” says Dr. Kammula. “TILs exist in a large number of patients, but they are suppressed because the body considers cancer part of itself — and the body doesn’t want to attack itself. That’s why the body has defense mechanisms that shut down immune responses like TILs. In addition, cancer itself is a very elusive foe. It can camouflage itself and put up defense mechanisms so that when a T-cell comes in and tries to attack it, the T-cell dies.”

Helping cancer fighters do a better job

Adoptive cell transfer harvests TILs directly from tumors, grows and expands the cells outside the body to circumvent the constraints of the body and the negative or immunosuppressive effects of the tumor, and then delivers them back to the patient with an accompanying lymphodepleting preparative regimen. “In a manner of speaking,” says Dr. Kammula, “it’s a brute force approach. It doesn’t rely on a drug to help the body produce TILs. It cuts out the middleman. It’s a very direct way of trying to install an immune system in patients who have advanced cancer.”

Dramatic regression

In initial clinical trials, this approach has achieved results that Dr. Kammula describes as surprising and encouraging. “In patients with metastatic uveal melanoma that has spread throughout the body, adoptive transfer of TIL can cause dramatic regression. In our first trial, published last year in Lancet Oncology, for a cancer that had virtually a zero percent response rate, we saw a 35 percet response rate with some very long term and complete responses.”

With these encouraging results in hand, Dr. Kammula brought his work to UPMC Hillman Cancer Center, opening a new trial in spring 2018 to replicate the initial results and set the stage for other investigations into the mechanisms and genetic factors leading to treatment response.

Engineering immunity

“We are going one step further with our research. We’re attempting to isolate the genes that are responsible for the TIL response,” says Dr. Kammula. “As we learn more about why certain patients respond to adoptive cell transfer, we hope to be able to generate a future treatment for those who can’t respond because they lack the potent TILs. In essence, we will try to give them what nature didn’t, through a process called T-cell receptor gene therapy.”

This will be accomplished in an offshoot program that the team is building. “We’ll be able to utilize all of the samples from our initial TIL trials to mine them for T-cell receptors. This will be a very important part of our ongoing research,” says Dr. Kammula.

Setting the stage

UPMC Hillman Cancer Center is an ideal place to find new ways to treat serious diseases like uveal melanoma and related cancers. In the near term, Dr. Kammula says, “We’ve built a cell manufacturing facility here. We hope to expand on it and start treating and generating cells for a variety of different cancers. We want to build the infrastructure and make Pittsburgh world renowned for cellular immunotherapy.” With the facilities, expertise, and network of UPMC, the blueprint for treating uveal melanoma could well be a blueprint for the future of cancer care.