ASCO, AACR Honor Immunotherapy Pioneer James Allison

Source: OncLive. May 2015

James P. Allison, PhD, who pioneered the checkpoint blockade strategy that led to the development of ipilimumab (Yervoy) and other immunotherapy agents, was recently honored with two prestigious awards: the Science of Oncology Award from ASCO and the Pezcoller Foundation–AACR International Award for Cancer Research.

The awards recognize not only his research accomplishments, but also the growing influence the field of immunotherapy has gained in the past few years, said Allison, a professor and chair in the Department of Immunology at the University of Texas MD Anderson Cancer Center, in an interview with OncLive.

“I am honored to be recognized by my peers for both of these prestigious awards,” said Allison, who also received a Giants of Cancer Care award from OncLive in 2014. “But more importantly, the fact that two organizations recognized someone for an advancement in immunotherapy really acknowledges that the field is here to stay now, and skeptics should take notice. These awards are not just about me, they are about everyone over the past few decades that has been working to use the immune system to treat cancer.”

Allison himself has been dedicated to understanding the immune system, and the specific role T cells play in it, for most of his career. In 1982, while he was working at MD Anderson Cancer Center (then named University of Texas System Cancer Center), he became the first scientist to determine how T cells recognize alien proteins within the body.

While continuing his research into T-cell response mechanisms, Allison discovered that blocking signaling of the immune-checkpoint protein CTLA-4 improved antitumor immune responses. His lab went on to develop an antibody against CTLA-4, which inhibited tumor growth in mice. This discovery led to the development of ipilimumab, which blocks the inhibitor function of CTLA-4, allowing T cells to attack and eliminate cancer cells. In 2011, ipilimumab became the first immune checkpoint inhibitor approved by the FDA when it was authorized for use as a treatment for patients with advanced melanoma.

The discovery of the immune checkpoint blockade strategy and the subsequent approval of ipilimumab have changed the course of Allison’s career.

“Before, my work was almost always about understanding the mechanisms of T cells and not specifically focused on cancer,” said Allison. “But I was interested in using the immune system to fight cancer, and whenever we found something unique I would try to investigate how it could be applied to cancer. The CTLA-4 discovery was the one that really showed the most promise. Since then, 80% of my lab has been focused on doing experiments related to CTLA-4 blockade.”

Ipilimumab has shown significant promise in the treatment of melanoma. Also, it is being investigated in several other tumor types.

In the trial that led to the approval of ipilimumab for patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment, overall survival (OS) was longer with ipilimumab alone compared with the experimental tumor vaccine gp100 (HR = 0.66; P = .0026). Patients treated with ipilimumab alone had a median OS of 10 months, while those treated with gp100 had a median OS of 6 months.

The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus gp100 compared with patients who received gp100 alone (HR = 0.68; P = .0004).

Recently, the FDA accepted a supplemental biologics license application for ipilimumab as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.

Combination therapies with ipilimumab are also showing promise. The phase II CheckMate-069 trial, which was recently presented at the 2015 AACR Annual Meeting, showed that nivolumab (Opdivo) plus ipilimumab delayed disease progression by 60% compared with ipilimumab alone in patients with advanced melanoma. The checkpoint inhibitor combination had an overall response rate (ORR) of 61% in a subgroup of BRAF V600 wild-type (WT) patients.

Multiple clinical trials have also been investigating ipilimumab with the oncolytic virus T-VEC, which was recently recommended for approval by the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC).

One phase Ib study showed an ORR with the combination of T-VEC and ipilimumab was 56% in patients with advanced melanoma.

Allison believes ipilimumab has the most potential when used in combination with other agents, but additional research is required before this can truly be successful.

“I think it is even more important now to understand the mechanism of these drugs in patients as it becomes clear that we have to start combining them,” said Allison. “We really have to know how things work if we are going to combine. We don’t want to give two things together that do the exact same thing or oppose each other. It is amazing to me how little understanding there is on the mechanisms of some of the up-and-coming checkpoint inhibitors.”

Allison’s lab is aiming to combat this lack of understanding by investigating checkpoint inhibitor combinations by pairing them with each other, as well as with oncologic viruses, radiation, targeted therapies, and chemotherapy.

He is also interested in checkpoint inhibitor combinations that can be used to treat tumors with lower mutation loads, such as those seen in kidney and prostate cancer.

“Checkpoint inhibitors have been mostly used in cancers with high mutation loads such as melanoma and lung cancer,” said Allison. “But in those cancers with lower mutational loads, there are still responses. I think we need to understand how we can use ipilimumab, for example, to lower the threshold so you can get responses to antigens that aren’t seen by the immune system unless you can target CTLA-4. That is the next challenge.”