How does immunotherapy work?
There’s no question that immunotherapy — the cancer treatment pioneered by MD Anderson’s Nobel Prize-winning chair of Immunology Jim Allison, Ph.D. — has earned a place among the pillars of cancer therapy.
The treatment, which frees the immune system to attack cancer, has produced remarkable results in cancers such as non-Hodgkin’s lymphoma, acute lymphocytic leukemia (ALL), melanoma and lung cancer. But it doesn’t work for everyone, and it can have varied results.
That’s why cancer researchers at MD Anderson are conducting clinical trials in which immunotherapy is combined with standard chemotherapies, antibody-based treatments and even other immunotherapy drugs. The institution’s blood cancer experts, in particular, are using combination therapies with great success.
FDA approves immunotherapy drugs for leukemia treatment
This past November, oncologists in the Leukemia department played a key role in clinical trials that led to the Food and Drug Administration’s approval of two drugs — glasdegib and venetoclax —for the treatment of acute myeloid leukemia (AML) in patients not eligible for intensive chemotherapy.
Glasdegib was approved following studies led by Jorge Cortes, M.D., and venetoclax was approved following trials led by Marina Konopleva, M.D., Ph.D.; Michael Andreeff, M.D., Ph.D.; Courtney DiNardo, M.D.; and Naval Daver, M.D.
Understanding and overcoming immunotherapy resistance
“Most immunotherapies are aimed at enhancing the patient’s existing immune system to ‘see’ and eliminate cancer cells, or by removing or overcoming barriers to this natural process,” says Loretta Nastoupil, M.D., assistant professor of Lymphoma and Myeloma. “There may be several reasons why these therapies sometimes fail. Understanding the mechanisms of resistance and potential strategies to overcome them is the focus of many efforts underway at MD Anderson.”
Nastoupil’s department alone has 138 clinical protocols that use one or more types of immunotherapies including immunomodulatory, immune checkpoint blockade, natural killer T cell, adoptive T cell, CAR T cell, monoclonal antibody, and cytokine, targeted and vaccine therapies.
MD Anderson’s Leukemia, Stem Cell Transplantation & Cellular Therapy departments, and the Pediatrics division, also are conducting numerous combination immunotherapy trials for blood cancers, including acute myeloid leukemia, chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS) and acute lymphocytic leukemia.
Farhad Ravandi, M.D., professor of Leukemia, is conducting a first-in-human study of the immunotherapy drug AMG 330 for relapsed or refractory (non-responsive to treatment) AML. The drug binds to a protein named CD33 that’s on the surface of tumor cells, and to a protein named CD3 that’s on the surface of T cells, and acts as a bridge bringing the cells close together, allowing the T cells to recognize and trigger the death of the tumor cells. The goal is to reduce the size of the tumor and slow the progression of the disease.
Early findings show that among the patients treated, two have had a complete response with recovery of blood counts after only one treatment cycle. These results are promising, but Ravandi cautions that testing of AMG 330 is still in its early stages.
Immunotherapy combinations show promise for myelodysplastic syndrome in clinical trials
Guillermo Garcia-Manero, M.D., professor of Leukemia, is studying the use of nivolumab or ipilimumab in combination with azacytidine to treat myelodysplastic syndrome, and is leading several myelodysplastic syndrome immune checkpoint therapy trials.
Through an alliance with Bristol-Myers Squibb, Garcia-Manero’s myelodysplastic syndrome study reported 68 percent of patients remained alive one year post-treatment after receiving a combination of azacytidine with ipilimumab. After a median follow-up of 20 months, the median survival for the azacytidine and ipilimumab group still had not been reached, which is important to note, Garcia-Manero says. Response rates were also higher than expected with single agent azacytidine.
“These agents demonstrated measurable activity in myelodysplastic syndrome as single agents and in combination with each other, with an acceptable toxicity profile and significant response and survival outcomes, particularly with ipilimumab,” Garcia-Manero says.
Amping it up with three-drug immunotherapy combinations
Most combination immunotherapy clinical trials involve two drugs. Some MD Anderson researchers, including Daver, an associate professor of Leukemia, are taking things a step further with three-drug trials. Daver is testing triple therapy for relapsed or refractory acute myeloid leukemia.
Through an alliance with Pfizer Inc., established through MD Anderson’s Strategic Industry Ventures department, cancer researchers at MD Anderson are being matched with multi-year, multi-disciplinary funding via the pharmaceutical industry. This alliance supports Daver’s testing of azacytidine with nivolumab and ipilimumab, an immunotherapy drug developed by Allison. The Pfizer alliance also includes such multi-therapy trials for solid tumor cancers, an effort headed by Aung Nain, M.D., associate professor of Investigational Cancer Therapeutics.
“We generally prefer clinical trials with combination therapy in myeloid malignancies like myelodysplastic syndrome and acute myeloid leukemia, as single-agent immune checkpoint therapy has shown little success,” says Daver. “For example, single-agent PD1 antibodies demonstrated limited to no efficacy in relapsed AML and MDS. However, we are seeing encouraging activity with azacytidine plus ipililumab in relapsed AML, and in newly diagnosed and relapsed myelodysplastic syndrome.”
Daver also oversees a study funded through another alliance with Bristol-Myers Squibb in which a triple therapy that combines two immune checkpoint inhibitors with azacytidine has shown promising results for treatment of relapsed or refractory acute myeloid leukemia.
Natural killer cells and non-Hodgkin’s lymphoma
Elizabeth Shpall, M.D., and Katy Rezvani, M.D., Ph.D., professors of Stem Cell Transplantation & Cellular Therapy, developed a technology to grow natural killer (NK) cells from umbilical cord blood. These cells fight invaders in the body, including bacteria, viruses and cancer. Pharmaceutical company Affimed N.V. is using this technology to develop drugs to treat non-Hodgkin’s lymphoma.
Many immunotherapy combination trials at MD Anderson are part of the cancer center’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into treatments that save patients’ lives. The Moon Shots Program includes a focus on blood cancers like acute myeloid leukemia, myelodysplastic syndrome, and B-cell lymphomas.
Low-dose chemotherapy and immunotherapy drugs
An evolving area of treatment that marries low-dose chemotherapy with immunotherapy drugs is showing promise for blood cancers, particularly for patients with newly diagnosed, or relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL). The outlook for these patients is poor and a transplant with stem cells from healthy donors remains the primary treatment.
However, a study of newly diagnosed patients by Leukemia department faculty Elias Jabbour, M.D. and Nicholas Short, M.D. showed that an antibody drug conjugate named inotuzumab ozogamicin produced promising results when combined with a drug named blinatumomab and a low-dose chemotherapy regimen named mini-hyper-CVD.
This triple-combination therapy appears to be safe and highly effective in elderly patients with newly diagnosed Ph-negative ALL, the researchers found.
Jabbour and Koji Sasaki, M.D., also with the Leukemia department, studied patients with relapsed Ph-negative ALL, and found the combination of inotuzumab ozogamicin – with or without blinatumomab – and low-intensity chemotherapy is effective.
Determining what works
Knowing what combination of immunotherapies and other treatments will likely be successful is a matter of how the body works, and perhaps a bit of serendipity.
“Tumor biology drives many decisions when deciding on optimal combination strategies,” says Nastoupil. “A little luck also is involved. Many times we’ll combine single agents together when we know the effectiveness and safety of individual drugs. Our rationale is that the combination will enhance the drug’s effectiveness.”
Nastoupil says the goal is to increase the number of patients likely to achieve a durable remission without impacting their quality of life due to untoward side effects.
“The best way to predict outcomes,” she says, “is to study the biology of the tumor, understand the mechanism of action of the drug, and have some preliminary data suggesting the combination will work.”
Some of the most promising combinations for patients with follicular lymphoma combine the drugs rituximab and lenalidomide. Nathan Fowler, M.D., and Michael Wang, M.D., both with the Lymphoma & Myeloma department, pioneered this treatment, as well as ibrutinib combined with rituximab for treatment of mantel cell lymphoma. In addition, Jason Westin, M.D., has explored a triple-drug therapy using rituximab, lenalidomide and ibrutinib prior to chemotherapy for a form of diffuse large B-cell lymphoma.
The sheer number of immunotherapy-based combination trials for blood cancers and disorders at MD Anderson is notable, with numerous faculty in several departments engaged in finding the combination of therapies most likely to work.
“We have great hope that combination approaches will continue to show promise as we further our understanding about tumor biology to predict a better outcome,” Nastoupil says.