Immunotherapy Moving into Prime Time

October 2016, Vol 7, No 9

New York, NY—At the Second International Cancer Immunotherapy Conference: Translating Science into Survival, immunotherapy pioneer Philip Greenberg, MD, Head, Immunotherapy Program, Fred Hutchison Cancer Research Center, Seattle, moderated a press discussion with several of the immunotherapy experts who presented at the conference.

“It took many years to move immunotherapy from the laboratory to the clinic,” said Dr Greenberg. “We spent several years refining immunotherapy for the clinic, which was a long, difficult slog. But once immunotherapy started working in the clinic, everything started to change,” he emphasized.

The panel included Jill O’Donnell-Tormey, PhD, Chief Executive Officer, Cancer Research Institute, New York; Elizabeth Jaffee, MD, Johns Hopkins, Baltimore; Alexander Huang, MD, Penn Medicine, Philadelphia; and Aung Naing, MD, FACP, University of Texas MD Anderson Cancer Center, Houston.

Significant Advances

“Since 1953, the Cancer Research Institute has supported research that has led to successful immunotherapies for cancer. We now have proof of concept that immunotherapy works for a subset of patients. What we’ve reaped is just the tip of the iceberg, and the possibility exists that immunotherapies can control and maybe someday cure cancer,” Dr O’Donnell-Tormey said.

She highlighted the 4 areas where immunotherapy is making significant advances, including:

  • Tumor microenvironment
  • Microbiota
  • Metabolism of immune cells at the tumor site
  • Neoantigens.

“We’re seeing significant advances in the tumor microenvironment. This morning we heard a great presentation that focused on the stroma, which is a major barrier for T-cells. We also need a better understanding of the function of T regs, myofibroblasts, and myeloid-derived suppressor cells in the tumor microenvironment. A second area we need a better understanding of is the microbiota, because it influences the nature and intensity of immune responses, and it also influences responses to current immunotherapies,” said Dr O’Donnell-Tormey. “The metabolism of immune cells at the tumor site can certainly affect T-cell function, and it is a third area where immunotherapy is making advances. For example, mitochondrial insufficiency represents a checkpoint that is possibly inhibiting anti-tumor immunity,” she said.

Dr Jaffee discussed neoantigens as another advancement in immunotherapies. “Neoantigens, which are the proteins that arise when the cell is mutating and becoming cancerous and metastasizing, is an area where immunotherapy is making noteworthy strides,” Dr Jaffee said. “Scientists are at the advent of developing vaccines that target these shifting proteins in an effort to make cancer cells more recognizable to the immune system.”

Dr Jaffee used a metaphor of a “brake” to describe the molecular mechanisms that obstruct cytotoxic T-cells from racing to a tumor site, and explained how immunotherapy is in the process of overcoming those braking mechanisms. A major obstacle for immunotherapy has been the development of checkpoint inhibitors that counteract the signals produced by cancer cells to suppress immune responses.

To date, the FDA has approved checkpoint inhibitors for PD-1 and CTLA-4, which have shown impressive efficacy in certain subsets of patients with cancer. Dr Jaffee surmised that immunotherapy will most likely add 10 to 20 checkpoint inhibitors to its armamentarium in the coming years.

“I think our progress in immunotherapy is analogous to our colleagues in the field of HIV 25 years ago. It wasn’t until scientists developed 3-drug combination therapies for HIV that patients could live normal lives without converting to AIDS. For cancer, we may need to target multiple tumor signals, so we will need combinations of checkpoint inhibitors to eradicate cancers that aren’t responding to current immunotherapies. Although vaccines haven’t proven to be efficacious with our current therapies, they may work to awaken killer T-cells. And after the T-cells are activated, we will combine the vaccines with 1, 2, or 3 checkpoint inhibitors that will enable them to actualize their full potential,” Dr Jaffee said.
<h3>Recent Trials Validating Advances in Immunotherapy</h3>
Dr Huang presented data from a recent study conducted with his colleagues involving pembrolizumab (Keytruda). “We set out to investigate whether or not we could monitor and predict the response of patients with stage IV melanoma to the PD-1 inhibitor pembrolizumab by tracking the effect of pembrolizumab on immune cells,” said Dr Huang.

He and his colleagues analyzed blood samples from 29 patients with stage IV melanoma taken before treatment and at 3, 6, 9, and 12 weeks after starting treatment with pembrolizumab. They then measured levels of the proliferation marker Ki67 in CD8-immune cells. Ki67 is a nuclear protein that plays a role in the regulation of cell division and is present at low levels in quiescent cells, but is increased in proliferating cells. After a protracted exposure to tumor cells, CD8 T-cells become progressively dysfunctional and elicit diminishing levels of Ki67. Consequently, by measuring Ki67 in patients with stage IV melanoma, Dr Huang and colleagues could determine whether pembrolizumab enhances the vitality of CD8 cells despite the previous progression of melanoma.

“We found that levels of Ki67 were significantly greater in 78% of melanoma patients after the administration of pembrolizumab. Thirty-eight percent of patients had a clinical response as measured by immune-related RECIST criteria. We were excited to find that patients with a pronounced immune response were more likely to have a clinical benefit,” Dr Huang told attendees.

“If validated in larger studies, Ki67 could prove to be an early biomarker to predict patient response to pembrolizumab and whether or not a patient should continue pembrolizumab treatment,” he added.

Dr Naing then discussed a phase 1 clinical trial he conducted with his colleagues on 2 combined immunotherapies used in 19 patients with advanced melanoma, renal-cell cancer, or non−small-cell lung cancer.

“In this clinical trial, we treated patients with 2 immunotherapies, pembrolizumab and AM0010. AM0010 is a pegylated form of the recombinant human cytokine IL [interleukin]-10, which has specific immune-stimulating effects that induce the activation, proliferation, and survival of CD8 cells,” stated Dr Naing.

Dr Naing added that the combination of the 2 immunotherapies was well-tolerated. Moreover, new and expanding T-cell clones were detected in the blood of all patients who received the combination therapy.

“After 10 to 15 months of observation, 2 of the 8 patients with renal-cell carcinoma had complete responses in the reduction of their tumor burden, and 2 had partial responses of 77% and 92% in tumor reduction, respectively. Of the 6 melanoma patients, 2 had partial responses and 2 others had an initial increase in tumor volume followed by a decrease. The results of this trial support proof of concept,” Dr Naing told attendees.

He added that the main limitation of the trial was its small number of patients, so AM0010 will have to be studied in larger populations to determine its efficacy.

Dr Greenberg concluded with a caveat regarding costs of cancer therapies. “Now that we finally have immunotherapy in clinical trials, we have to contend with escalating costs, and those resources are still quite limited,” he said.

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