Immunotherapies Rock the House

The response to immunotherapies was overwhelming.

“I remember a similar such session at AACR about seven years ago,” said current AACR (American Association of Cancer Researchers) session moderator, Mario Sznol, MD, Yale School of Medicine, addressing a packed house. “And that room had about 30 people in it—so I guess that says something about the potential of the technology.”

Potential indeed: Dr. Sznol was speaking at an educational session held a day before the conference even officially began.

AACR president, Carlos L. Arteaga, Vanderbilt University School of Medicine, was also keenly aware of the trend. “Immunotherapies are hot now,” he said. “Basically, there was a confluence of results of positive trials with immune therapies last year and we are now seeing the refinement of those trials.”

The new data are particularly striking for their clinical results—reporting once uncommon at this basic research meeting. “If you go back ten years you would not see emphasis on clinical trials in AACR,” said Dr. Arteaga. “This is new.”

Patient, Heal Thyself

Leading the clinical charge was Steven Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute. Speaking at the plenary session, Dr. Rosenberg gave an overview of his work, as well as current results for the therapeutic use of patient-derived, tumor infiltrating lymphocytes (TILs) an approach known as “adoptive cell therapy”.

The method in brief: Excise a portion of patient’s tumor; identify within that tissue immune cells (T lymphocytes, or T cells) that have antitumor activity; expand that antitumor T cell population in vitro; reintroduce that population back in to the patient.

This approach has been particularly effective in treating advanced melanoma; Dr. Rosenberg, working in collaboration with Lion Biotechnologies, presented data for his most successful study in this setting.

Results from a phase II study of 101 patients demonstrated an objective response rate (ORR) of 54% after treatment with TILs. This finding represents a significant improvement over the recently approved immunotherapy, ipilimumab that has ORRs of less than 45%.

“There were 20 complete responders,” Dr. Rosenberg reported, “With 19 of 20 having ongoing response out to 124 months.” This is an extraordinary outcome for patients who otherwise would have died.

Targeted Approach

Of note, Dr. Rosenberg does not know what specific melanoma antigens his TILs are reacting to—quite possibly more than one epitope. That uncertainty is not present in the work of Mark Middleton, M.D., Ph.D., professor of experimental cancer medicine at the University of Oxford, UK.

Speaking at an AACR press conference, Dr. Middleton presented his data for the bi-specific, T cell receptor/antibody construct, IMCgp100, manufactured by Immunocore.

The drug has two components. The first is comprised of a monoclonal T cell receptor sporting the melanoma antigen glycoprotein (gp) 100. The second component is an anti-CD3 peptide, which, after IMCgp100 binds to its tumor target, recruits killer T cells to mount a full-on immune system attack. 

Dr. Middleton reported the first-in-man results for this novel compound in a dose-ranging study that enrolled 31 patients with advanced melanoma. Of the 16 patients who received more than 135 ng of IMCgp100 per kilogram and were evaluable, three had partial responses.

Mindful that most phase I dose-ranging studies do not merit response reporting, Dr. Middleton was bullish on the outcome. “I think this is very exciting, not least because there’s a potential to combine IMCgp100 with some of the other recently developed immunotherapeutics.”

A CAR and Driver

Yet another new avenue for immune-based therapeutics is being exploited by CARs (chimeric antigen receptors), a technology very similar to that of Dr. Rosenberg’s adoptive cell transfer.

“A patient’s T cell can be targeted to a tumor through the introduction of a chimeric antigen receptor,” explained Renier Brentjens, MD, PhD, director of the cellular therapeutics center at Memorial Sloan Kettering Cancer Center, and a cofounder of Juno Therapeutics.

In the present study, Dr. Brentjens engineered CARs to co-express not only CD19, an epitope expressed by tumor cells in the setting acute lymphoblastic leukemia, but as well, the immune system signaling CD28.

Results for 22 patients with ALL treated with CARs showed complete remission rates of 82%. “These patients had very poor prognosis going in to the trial and had already failed prior therapy.”

Of note, two patients died shortly after treatment initiation, attributed to a CAR-induced “severe cytokine release syndrome”.

These events—which led to a twitter storm amongst researchers attending the AACR meeting—suggest that the CAR method may need tweaking.

One such tweaked approach is being explored by Cellectis Bioresesearch, a method that uses allogeneic T cells—cells from healthy donors. These cells are equipped with a "suicide gene", a kill switch to turn off the therapy should the patient have a serous adverse reaction. This approach may skirt the issues encountered by Dr. Brentjens, and would turn what is now a patient-specific procedure in to an off-the-shelf, readily available drug.