Immunotherapy

By Helen K. Kelley

In recent years, immunotherapy – a range of cancer therapies that use the body’s own immune system to attack cancer cells – has gained ground as a weapon for fighting many different forms of the disease. We recently spoke with two Atlanta physicians about the promise and the reality of some immunotherapies.

Targeted Therapies Block Growth and Spread of Cancer
Kenneth Braunstein, M.D., an Atlanta hematologist affiliated with Northside and Saint Joseph’s hospitals, says that precision medicine – predicting more accurately which treatment and prevention strategies for a particular disease will work based on individual genes, environment and lifestyle – is a hot topic right now in the field of hematology and cancer treatment.

“What precision medicine means for immunotherapy is that we’re looking for the driver genes of cancer. The problem is that there are different types of driver genes for various diseases. While some of those driver genes are well characterized and understood, such as for sickle cell and Parkinson’s diseases, the driver genes in cancer cells are not so well defined,” he explains. “And the big question about driver genes is, if you eliminate a particular gene, will that cure the cancer?”

There is some evidence to support this elimination theory. For example, tyrosine kinase inhibitors are being used to successfully block cell reproduction in T-cell non-Hodgkin lymphoma.

“We’re seeing that these patients show no evidence of disease after 10 years. They’ve stopped therapy, and, so far, they are not coming back,” Braunstein says. “So, in this case, the evidence points to the idea that if you can block the reproduction of cells, you can cure the disease.”

Another therapy, CAR T, has shown promise but has produced mixed results in patients who have received it. CAR T attempts to remove all cancer cells by attaching a virus that binds to T-cells and programming those cells to attack a particular target. When it works, Braunstein says the results are dramatic.

“It’s like an atom bomb; it just clears everything,” he says. “But the problem with CAR T is that we now have patients who can show us long-term follow-up. About half of them have a recurrence at about two years. It’s not clear whether CAR T can become the magic bullet we had hoped it would be. It can be the atom bomb, but to get to zero cancer cells, we may need the hydrogen bomb.”

Braunstein encourages physicians to learn more about targeted therapies and be aggressive in referring their patients to specialists who may know of clinical trials that would be appropriate.

“For the right patients, a targeted therapy may well be the best way of getting them to the point of zero minimal residual disease or close to it,” he says.

Checkpoint Inhibitor Therapy for Effective Immune System Response
“We are truly at a historic juncture with the addition of immunotherapy as a weapon in fighting cancer,” says Aaron Alizadeh, M.D., a hematology/oncology specialist and researcher with Georgia Cancer Specialists.

“Over the last several years, there has been an enormous increase in the understanding of and research into the immunologic underpinnings of cancer – how the immune system detects cancer and vice versa, and how cancers are able to evade the immune system.”

Alizadeh says that checkpoint inhibitor therapy, one of the newer immunotherapies, has proven to be a very effective form of treatment for certain tumors. The therapy employs two main classes of drugs – those that target the CTLA-4 receptor (ipilimumab), and those that target PD-1 antibodies (pembrolizumab). It plays into the natural checks-and-balances scheme of the immune system, enabling it to recognize the tumor and mount an effective immune response to kill the tumor.

Checkpoint inhibitor therapy was first successfully used in the melanoma arena.
“The reason melanoma was chosen as the first type of cancer to be treated with checkpoint inhibitor therapy is that it is a very immune-responsive disease,” Alizadeh says. “Recent data shows that melanoma has a proclivity to go to the brain, and when it does, the results are devastating and deadly. Recent clinical trials showed that checkpoint inhibitor therapy is effective at penetrating the central nervous system for tumor involvement there.

He adds that the treatment is now being used on other types of tumors.

“As a result of checkpoint inhibitor therapy’s success in treating melanoma, many other tumor types have been identified that are also responsive. It works on lung, kidney, bladder, liver and Hodgkin lymphoma, and some forms of colon cancer also respond readily,” he says. “It’s been a matter of identifying the right kind of treatment for the right kind of cancer.”

Clinical trials hold the key to a better understanding of how checkpoint inhibitor therapy can be used in treating different forms of cancer, including duration of treatment, side effects and more.

“Although we’re just in the infancy of this form of therapy, the future is bright,” Alizadeh says. “However, there is much more to understand and to be tested, … and there are a lot of questions that need to be answered.”

Novel Cancer Vaccine Strategy Blocks Death of Tumor-specific Cytotoxic T cells
New research published in Cancer Immunology Research by Drs. Esteban Celis and Hussein Sultan of the Georgia Cancer Center at Augusta University could serve as the stepping- stone in constructing vaccines with a greater likelihood of finding and attacking tumors in the human body.

According to Celis and Sultan, the key in this vaccine strategy is increasing the amount of time a cytokine called interleukin 2 (IL-2) stays in the body. IL-2 is a molecule in the immune system responsible for regulating the activity of some white blood cells known as killer T cells.

“After administering peptide-based vaccines in mouse models of cancer, we saw that sustained IL-2 signaling dramatically increased the number of tumor-specific cancer-killing Tcells (CD8+),” says Dr. Sultan, a postdoctoral fellow in the laboratory of Celis, leader of the Center’s Cancer Immunology, Inflammation and Tolerance Program.

During their experiments, Celis and Sultan noticed there was also an increase in the T cells’ ability to resist cancer immune evasion caused by a protein called programmed deathligand 1 (PD-L1). It is well known that the PD-L1 protein can be produced by tumor cells, allowing them to evade destruction by the killer T cells.

“Together, these results substantially improved the anti- tumor efficacy of peptide-based vaccines in tumor-bearing mice,” Sultan says.

“To be effective, IL-2 needed to be administered either as a complex of IL-2 and anti-IL-2 antibody, or in the form of polyethylene glycol-modified IL2 (PEG-IL-2),” Celis adds. “These formulations prolonged the half-life of IL-2, allowing sustained activation of the IL-2 receptor on vaccine-generated T cells, allowing them to survive longer in the body and attack the tumor.”

According to Celis, it is difficult for vaccines to induce antibodies against tumors because most of the tumor antigens are not foreign proteins, as is the case with viruses. On the other hand, T cells have the capacity to recognize other types of antigens.

“As we know, cancer cells are created when normal cells undergo certain mutations,” Celis says. “So, they don’t al- ways look foreign to our immune system.”

Both Celis and Sultan hope their observations in mouse models of cancer can find their way into clinical studies with human cancer patients.