Immunotherapy Techniques Are Being Explored in Gliomas

Immunotherapies are among the most promising techniques in oncology, but so far, they are largely unavailable to patients with brain cancer.

Many of these approaches are, however, being studied both in labs and in clinical trials, and the growing understanding of what works, what doesn’t and why provides a basis for hope that immunotherapy will eventually play a role in the treatment of gliomas.

Laying Out the Possibilities

Four researchers gave an overview of the state of that field during a Nov. 17 session at the 22^nd Annual Meeting and Education Day of the Society for Neuro-Oncology, in San Francisco.

The immunotherapeutic strategies being explored for the treatment of gliomas fall into four categories, explained Duane Mitchell, M.D., Ph.D., co-director of the Preston A. Wells Jr. Center for Brain Tumor Therapy and director of the University of Florida Brain Tumor Immunotherapy Program.

1. Vaccines can boost the body’s ability to fight antigens, molecules that are perceived by the immune system as toxins or invaders. Studies have shown that this approach can safely generate immune responses.
2. Adoptive cellular therapy can mean the use of tumor infiltrating lymphocytes (TILs) or chimeric antigen receptor (CAR) T cells. In these techniques, cancer-fighting T cells are removed from a patient, multiplied in a lab and then returned to the body. In CAR therapy, the T cells are engineered to hone in on the cancer before they are reinfused.
3. Checkpoint inhibition uses medicine to block immune-suppressing proteins that are naturally made by the body. This frees up immune cells to fight harder against cancer.
4. Oncolytic viruses, either natural or engineered, induce an immune response by invading and killing cancer cells while ignoring healthy cells.

Seeking Targets for Vaccines

All these techniques depend on scientists’ understanding of what drives a particular cancer and their ability to figure out which mutations, if silenced by medication, would lead to the slowing or eradication of the disease.

Vaccines against brain cancer fight antigens that occur due to genetic mutations or because the disease overexpresses them, explained Hideho Okada, M.D., Ph.D., a professor in the Department of Neurosurgery at UCSF. Those that arise from mutations to genes such as EGFRVIII tend to be present only in limited numbers of gliomas, but when they appear, they can offer the opportunity to create personalized vaccines. Antigens that arise from overexpression of proteins such as IL13-R alpha 2 and WT1 are present in most gliomas, and may thus may lend themselves more to commercial development of vaccines, Okada said.

That said, some mutation-caused antigens are common enough to hold promise in the widespread treatment of gliomas. One that looks promising as a target is the H3.3K27M mutation, which is present in more than half of these cancers and associated with shorter survival, Okada said.

Finding the Best CARs

In addition, he said, mutations to the IDH1 gene occur early in the development of low-grade glioma, which could make them a good target for a vaccine.

In the area of CAR T cell therapy for brain cancer, the search is also on for the best mutations to target. Mitchell mentioned one study of a CAR therapy targeting IL13-R alpha 2, and noted that the drug succeeded quite well, but only when infused directly at each tumor site.

“There was no long-term, durable response, but it (generated) the first complete response of glioblastoma using a CAR therapy,” he said.

Another potential target for CAR T cell therapy in glioblastoma is the antigen CD70, a strategy being explored by Mitchell and his colleagues. This antigen is naturally produced by the body, but some cancers generate too much of it. In people with glioblastoma, there tend to be high amounts of CD70 in cancer cells but none in normal brain cells, which suppresses the immune system, Mitchell explained.

CAR T cell therapies that target CD70 have been able to recognize glioblastoma in cell lines and have worked in mice; they will soon be tested in people in clinical trials, Mitchell said. He noted that engineering CD70 CAR T cells to include molecules known as chemokine receptors seems to make them even more effective against brain tumor cells.

Inhibiting Checkpoints

“The mechanisms are still being investigated, but there is potential,” he said.

Checkpoint inhibitors, approved for diseases including renal cell carcinoma, melanoma and lung cancer, improve overall survival in about one-third of eligible patients. In gliomas, preclinical data suggest that inhibitors of the checkpoint proteins CTLA-4 and PD-1 could work, but there are some challenges, said Michael Lim, M.D., director of brain tumor immunotherapy and professor of neurosurgery at Johns Hopkins Medicine.

Glioma tumors express more of the protein PD-L1 as they progress to higher grades, and it had been thought that this would make them responsive to PD-1 inhibitors. Disappointingly, the CheckMate-143 trial did not show improved survival in these patients using the drug Opdivo (nivolumab), “but I think there’s something to it, and other trials are pending” that will consider such medications given differently, including to newly diagnosed patients and in combination with other treatment strategies, Lim said.

He added that the proteins LAG-3 and TIM-3 may make good targets for checkpoint inhibitors in gliomas. LAG-3 inhibition seems synergistic with PD-1 inhibition, and that combination is being studied in a large clinical trial, along with a drug that inhibits the protein CD137, he said.

Lim mentioned the concept of “hot” tumors, which have intrinsic and extrinsic factors that make them responsive to checkpoint inhibitors, and “cold” tumors, which are less responsive. He said that gliomas may be “cold” tumors, for one thing because they have a low frequency of cancer-driving mutations. However, techniques to increase T cell infiltration into “cold” tumors are being explored, added Derek Wainwright Ph.D., assistant professor at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

Another concern about the success of immunotherapies in brain cancers, Lim noted, is that standard-of-care treatment may interfere, since the chemotherapy Temodar (temozolomide), radiation and steroids are all generally immunosuppressive. Tweaking standard-of-care treatment is one possible way of dealing with this problem, Lim said.

Speakers also pointed to other potential challenges with checkpoint inhibition:

• In patients with glioma, some T cells become “exhausted” and unable to respond to checkpoint inhibitors, Lim said. Solutions could involve finding ways to revive these T cells or targeting different T cells, he said.
• Gliomas are characterized by the presence of many myeloid cells, which cause immunosuppression. This could be a barrier to immunotherapy, but finding ways to activate the myeloid cells, as well as treating with PD-1 inhibitors, may help, Lim suggested.
• The protein IDO1, which is highly expressed in glioma, also causes immunosuppression, Wainwright said. He suggested exploring the combination of an IDO1 inhibitor, a PD-1 inhibitor and radiotherapy.

Considering Age

Despite all the progress toward the use of immunotherapeutic agents in gliomas, there is a caveat, Wainwright warned.

In mice, it seems that younger age predicts better success with these drugs. That’s a problem, Wainwright said, since the median age of patients with glioblastoma is 64.

“Old age decreases the efficacy of immunotherapy against glioblastoma,” he said.