Immunotherapy gets top billing at AACR

The G.H.A. Clowes Memorial Award is the oldest honor bestowed on a researcher by the American Association for Cancer Research. It's been given by the AACR and Eli Lilly and Company since 1961 to recognize an individual with outstanding recent accomplishments in basic cancer research.

The 2014 honoree – James Allison, Ph.D., chair of Immunology and executive director of the immunotherapy platform at MD Anderson – received his Clowes award at the AACR annual meeting, a gathering inundated this year with presentations about the latest in cancer immunotherapy. Allison and other scientists at AACR 2014 recalled when immunotherapy talks were few in number and drew only a handful of participants. But that was before Allison applied his basic-research findings on the biology of T cells to invent a completely new approach to treating cancer by blocking the CTLA-4 molecule on T cells that shuts down an immune response, protecting tumors from T cell attack.

Approval of his drug ipilimumab in 2011 for metastatic or unresectable melanoma — the first therapy to ever extend survival of these patients — launched immune checkpoint blockade as a new approach.

"Immunotherapy for cancer is really just beginning," Allison said after his Clowes lecture. "As we learn more and develop immunotherapy drug combinations, we can start thinking about curing cancer in many patients."

This year's annual meeting featured:

• 331 abstracts on immunology or clinical immunology presented in 14 poster sessions and one minisymposium
• Of these, 96 covered tumor immunobiology, 192 cancer immunotherapy and 43 reported clinical research results.
• 39 invited talks in plenary sessions, major symposia, mini symposia and several standing-room-only educational sessions with hundreds of attendees.
• Three AACR awards to immunotherapy experts.

Presentations included preclinical research on a number of new targets, as well as clinical trial results for melanoma and other types of cancer, including non-small cell lung cancer, by researchers from multiple cancer centers.

"Dr. Allison is a pioneer in the fields of immunology and cancer immunotherapy," said Margaret Foti, Ph.D., M.D., (h.c.), chief executive officer of the AACR. "His decades of ground-breaking basic research on T-cell development and function laid the scientific foundation for the development of a class of revolutionary immunotherapies that are transforming the lives of many patients with melanoma and offering hope to patients with several other forms of cancer. Dr. Allison's inspirational career showcases how basic scientific discoveries can lead to lifesaving clinical advances, and he is, therefore, greatly deserving of this honor."

Allison's lecture noted a number of developments:

• Long-term survival of three years or more for 22% of patients with advanced melanoma who received ipilimumab in clinical trials or compassionate-use programs before the drug's approval by federal regulators in 2011, a study reported by Steven Hodi, M.D., of Dana-Farber Cancer Institute.
• Combining ipilimumab with the investigational drug nivolumab, which targets immune checkpoint PD1, increased the response rate to half of patients with advanced melanoma in an early clinical trial led by Jedd Wolchok, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center. The combination has moved on to a phase 3 trial.
• Mouse model research confirms the co-stimulatory effect of ICOS, a molecule on T cells found to be associated with longer survival in patients treated with ipilimumab in clinical research by Padmanee Sharma, M.D., Ph.D., associate professor of Genitourinary Medical Oncology at MD Anderson. Knocking out ICOS reduced the efficacy of ipilimumab in mice with melanoma by 50%. Adding ICOS to ipilimumab and a B16 vaccine increased survival to 85%.

Oncolytic virus + anti-CTLA hits distant tumors

Allison also shared results of a preclinical study combining treatment with the cancer-killing Newcastle disease virus with ipilimumab, initially reported in Science Translational Medicine. Research in Allison's lab launched while he was at MSKCC and continued in Wolchok's lab found that injecting NDV into a melanoma tumor in mice triggers an inflammatory effect in other tumors without any sign of the virus itself having spread to them. Tumor growth was delayed, and about 10% of treated mice survived.

This led Allison and post-doc Dmitriy Zamarin to hypothesize that combining anti-CTLA-4 blockade with NDV would boost the T cell response to tumors aside from the one injected with the virus. This combination increased distant tumor immunity to the extent that 80 percent of treated mice survived.

These results were replicated in a mouse model of the poorly immunogenic TRAMP C2 prostate cancer, which is less vulnerable to oncolytic viruses, indicating the combination's effect is achieved through tumor immunity rather than direct cellular destruction by the virus.

Tumor infiltrating lymphocyte levels in distant tumors increased dramatically, with T effector cells accounting for the increase while levels of immunity-suppressing T regulatory cells did not change.

Allison reported similar results combining NDV with ICOS stimulation.

"With the discovery of additional immune checkpoints such as PD1, LAG-3 and others, T cell activation turns out to be a lot more complex than we thought in the mid-90s," Allison noted during his lecture. "But we're beginning to understand how these molecules work together and how combination therapies will improve the efficacy of immunotherapy."

Too much CTLA-4 overcomes ipilimumab

While ipilimumab dramatically helps a substantial group of patients, understanding why it's not effective for others is an important research focus. MD Anderson scientists presented research showing that one problem is simply too much expression of the checkpoint blockade molecule CTLA-4 that is targeted by the drug.

The team analyzed possible biomarkers to predict antitumor activity in 81 patients with resistant, metastatic melanoma. They analyzed via immunohistochemistry the levels of CTLA-4, PD1, PD-L1, phosphorylated AKT, pS6, fas-l, Ki67 and BRAF V600E on pre-treatment tumor samples and correlated them with outcomes.

"High levels of CTLA-4 in both tumor-infiltrating lymphocytes and in the tumors themselves correlated with poor overall survival," said Nitin Chakravarti, Ph.D., instructor in Pathology.

Since patients were treated with the maximum-tolerated dose of ipilimumab, the implication is that CTLA-4 expression on some T cells simply overwhelms the ability of the drug to block them all, stifling the immune response and leading to disease progression.

This study did not attempt to discern the cutoff levels of CTLA-4 expression, or any of the biomarkers, that would suggest reduced effectiveness of treatment.

The researchers also found that high expression of pAKT in the tumor also correlated with poor outcome. Low expression of pAKT and CTLA-4 in tumors correlated with better survival. "pAKT indicates an activated PI3K pathway, underlining that tumor cells use more than one pathway to escape cell death," Chakravarti noted.

Their findings suggest other targeted therapies and drug combinations might address resistance. Senior investigators on the project are Wen-Jen Hwu, M.D., Ph.D., professor of Melanoma Medical Oncology, and Victor Prieto, M.D., Ph.D., professor and interim chair of Pathology.

Hwu is also a co-author on another study presented at AACR showing that outcomes of treatment of melanoma with PD1 inhibitor is correlated to the expression of its ligand, PD-L1, in the tumor.

Combining adoptive T cell therapy and anti-CTLA-4

Cassian Yee, M.D., professor in Melanoma Medical Oncology, presented results from a clinical trial that treated 10 metastatic melanoma patients with antigen-specific T cells primed and expanded in vitro with interleukin-21 and ipilimumab.

In this first-in-man study, four patients experienced objective responses (two continuous complete responses and two partial remissions [PRs]), and three others had stable disease at 12 weeks. Patients also developed immune responses to other tumor antigens not targeted by the injected T cells.

Yee presented the results during a special session to update results of Stand Up to Cancer Dream Teams. Yee is on the immunotherapy dream team led by Allison.

The promising combination therapy trial was conducted when Yee was at Fred Hutchinson Cancer Research Center in Seattle. Now director of the Solid Tumor Cell Therapy Program at MD Anderson, Yee is organizing follow-up clinical trials of this and other combinations.