Tomas Sandoval was about to become a father for the second time in June 2014, when he was devastated to learn he had non-Hodgkin lymphoma, a type of cancer that starts in the white blood cells. The College Station, Texas, resident underwent a stem cell transplant at MD Anderson that kept his disease in check – for a year.
In June 2015, doctors discovered a large chest mass that revealed Sandoval’s cancer had spread. With few options left, he joined a clinical trial testing CAR-T cell therapy for the treatment of lymphoma. Led by Sattva Neelapu, M.D., professor of Lymphoma and Myeloma, the study is the first multi-center trial of its kind for lymphoma.
“It saved my life. The mass disappeared within a week, and by three weeks I was in remission,” says Sandoval. “Although I knew the therapy could cause serious side effects, mine were minor. Other patients I have talked with all said they would do it again because it works.”
How it works
In CAR-T therapy, a person’s own T cells – disease-fighting immune cells – are removed and sent to a lab where they are genetically re-engineered to produce chimeric antigen receptors (CARs) on their surface. CARs are proteins that allow T cells to recognize cancer.
The CAR T cells are then multiplied in the laboratory until there are millions. Next, they’re sent to the hospital and infused back into the patient’s bloodstream. These “attacker” cells not only recognize and kill cancer cells, but they may remain in the body long after the infusion has been completed and guard against cancer’s recurrence.
“Patients with aggressive non-Hodgkin lymphoma whose disease has failed at least two lines of therapy have a major unmet need in terms of available therapies that can induce long-term remission, and there has been no new treatment for over 20 years,” Neelapu says. “Their prognosis is often poor with an average survival of six months. We hope this therapy will be a solution and perhaps even curative for some patients.”
So far, the CAR-T cell drug Neelapu is testing, known as KTE-C19, has shown a six-times higher complete remission rate than standard treatment. The drug is currently under review by the Food and Drug Administration.
Healing the physician
CAR-T cell therapy is part of a growing field of cancer treatment called immunotherapy, a broad term that covers a range of treatments that harness patients’ immune systems to fight cancer. Other forms of immunotherapy to treat cancer include monoclonal antibodies, which are designed to attach a very specific part of a cancer cell; vaccines, which stimulate an immune response against cancer; and immune checkpoint inhibitors, which take the “brakes” off the immune system so it can recognize and attack cancer cells.
Immunotherapy has proven successful in many cancers such as melanoma, lung and kidney cancer, and Hodgkin lymphoma with several drugs already FDA-approved. And with more than 65 trials underway to test immunotherapy’s effectiveness in battling blood cancers such as chronic lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma and acute myeloid leukemia, MD Anderson is considered a leader in the field.
“Most major cancer centers have two or three leukemia trials using immunotherapy,” says Naval Daver, M.D., associate professor of Leukemia. “We have more than 15, and are very much out front. It’s an exciting area of study and we are seeing some encouraging results in patient responses.”
Immunotherapies are made even more effective by rationally combining them with other types of cancer treatment in some patients, like Thomas Lombardo of Beaumont, Texas.
Once near death, Lombardo has returned to his beloved golf game, something he thought would never be possible again. In December 2015, the 89-year-old cardiologist was diagnosed with acute myeloid leukemia. When chemotherapy failed to work, he enrolled in a clinical trial led by Daver.
“Mr. Lombardo was placed on a combination drug study using the epigenetic drug Vidaza, which interferes with the growth and spread of cancer cells, and the immune checkpoint drug nivolumab, which activates a patient’s T cells to target cancer cells without damaging normal ones,” says Daver. “He’s done very well.”
Fourteen other patients on the trial are alive and well beyond one year.
“This is outstanding, considering the median survival for relapsed AML is about four to five months,” Daver says. “We believed this could be improved by adding another immunotherapy, ipilimumab, and recently have started a triple-agent study of Vidaza with nivolumab and ipilimumab for patients with AML.”
As Lombardo continues to participate in the trial, his quality of life has already improved. He’s back to working part time in his father-son medical practice, and enjoying his three children and nine grandchildren.
“I see what goes on at MD Anderson and it’s fantastic to see how big the cancer center is, and how well everyone is treated,” Lombardo says. “The quality of care is world-renowned and that’s why I came here.”
MD Anderson has been a leader in collaborating with biopharmaceutical companies to aggregate investigations and accelerate new discoveries for cancer, an effort coordinated by the Department of Strategic Industry Ventures, led by Ferran Prat, Ph.D., senior vice president. A few of the alliances include:
MD Anderson and Pfizer signed an agreement in 2017 to develop novel immune therapies beyond PD1 and CTLA-4 with next-generation immune checkpoints such as OX40, 41BB and combinations of these with molecular and monoclonal antibody therapies. The studies, led by Naval Daver, M.D., associate professor of Leukemia, will be the first eight-armed “octopus” trial in AML. Daver is working with Andrew Futreal, Ph.D., chair of Genomic Medicine and Ignacio Wistuba, M.D., chair of Translational Molecular Pathology.
MD Anderson announced an agreement with Bristol-Myers Squibb in 2014 to evaluate multiple immunotherapies for acute and chronic leukemia and other hematologic malignancies. The therapies include nivolumab, ipilimumab and three early-stage agents developed by Bristol-Myers. The collaboration is led by Hagop Kantarjian, M.D, chair of Leukemia, along with Jim Allison, Ph.D., chair of Immunology, and Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology, co-leaders of the immunotherapy platform of the Moon Shots Program™. The agreement, which has already resulted in several published studies and presentations on combination immunotherapies, allowed for 10 simultaneous investigations led by different researchers.
MD Anderson and Affimed N.V., a clinical stage biopharmaceutical company, have a clinical development and commercialization collaboration to evaluate Affimed’s TandAb technology in combination with MD Anderson’s natural killer cell product. Read more about the NK cell research being done by Katayoun Rezvani, M.D., Ph.D., and Elizabeth Shpall, M.D., below.
Astellas Pharma Inc.
MD Anderson is working with Astellas Pharma Inc. to research and develop a new treatment for AML patients. Read more about the collaboration, which focuses on a humanized monoclonal antibody invented by Jeffrey Molldrem, M.D., below.
A look at other blood cancer immunotherapy studies
MD Anderson is conducting several dozen clinical trials involving investigators from multiple departments, programs and other institutions and companies that are studying various immunotherapy agents for blood cancer.
Here are some highlights:
Guillermo Garcia-Manero, M.D.
professor of Leukemia
Garcia-Manero co-leads MD Anderson’s MDS/AML Moon Shot™ along with Hagop Kantarjian, M.D., chair of Leukemia. Garcia-Manero is studying various combinations of immunotherapy drugs such as azacitidine (AZA), nivolumab and ipilimumab in patients with previously treated or untreated MDS. Hypomethylating (HMA) agents such as AZA have been a front-line therapy for patients with higher-risk MDS, but are not always effective. Garcia-Manero and other MD Anderson investigators are studying whether combination immunotherapy can be more affective. He found that PD-1 blockade in combination with AZA in untreated MDS patients is associated with tolerable side effects and clinical activity. His studies have shown that ipilimumab alone induced responses in previously treated patients, while nivolumab alone did not show clinical activity. Garcia-Manero is working closely with Bristol-Myers Squibb in a collaboration involving a number of clinical trials for different types of leukemia, including MDS.
Jeffrey Molldrem, M.D.
professor of Stem Cell Transplantation
Molldrem identified an HLA-restricted peptide called PR-1, which is expressed on leukemia cells, and has created a humanized monoclonal antibody called h8F4, which targets a peptide expressed in cancer cells and cancer stem cells. h8F4 is under study as a safer yet more potent therapy for aggressive AML. He’s working with Carlo Toniatti, M.D., Ph.D., executive director of MD Anderson’s Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, and through a collaboration with Astella’s Pharma Inc.
Katayoun Rezvani, M.D., Ph.D., and Elizabeth Shpall, M.D.
professors of Stem Cell Transplantation
Rezvani and Shpall are studying natural killer (NK) cells, white blood cells that monitor the body for infectious and cancerous cells. The technology to grow NK-cells from umbilical cord blood was developed at MD Anderson. In January 2017, MD Anderson teamed with Affimed N.V. to leverage Rezvani and Shpall’s expertise in NK cells and translational medicine and Affimed’s capabilities to develop tumor-targeting bi-specific TandAb immune cell engagers. The investigators will study whether the combination of their expertise in NK cells and Affimed’s technology will result in a novel cellular therapy for Hodgkin Lymphoma. AFM13 is being developed both as monotherapy and in combination with other therapeutics.