BMT and Cell Therapy Division Leads Advances in Cancer Treatment

The astonishing advances in cancer treatment taking place at Stanford were on display on October 1, 2022, as 400 cancer survivors and their families celebrated life, at the Blood and Marrow Transplant (BMT) & Cellular Therapy division’s annual reunion. They were joined by many of the 500 members of the division, all of whom participated in caring for the former cancer patients. The event also marked the first in-person reunion for cancer survivors at Stanford since 2019.

David Occhipinti, 69, attended  the event. He was the first BMT patient treated at Stanford, in 1987. After being told at the time that he had two weeks to live, he told his physician that he intended to beat this thing. "Well,” he says, “thirty-five years later, I’m still here. I will be forever grateful to the doctors, nurses, and staff that supported me during my very difficult ordeal.”

Since its founding in 1987 by the late Karl Blume, MD, the BMT division has become an international leader and a source of innovation in BMT and cell therapy treatments.

David Miklos, MD, became division chief in 2020, succeeding Robert Negrin, MD, who served in that role for 20 years beginning in 2000. “We decided to add ‘Cell Therapy’ to the name of our division since so much of our work now involves the new technology of cellular engineering,” says Miklos.

“Our patients are our partners in all our endeavors,” he adds. “They are willing to go through a high-risk transplant to get their lives back, and most want to share their experiences to benefit future patients.”

Crystal Mackall, MD, PhD, is the Ernest and Amelia Gallo Family Professor of Pediatrics and Internal Medicine, and is founding director of the Stanford Center for Cancer Cell Therapy. She works closely with colleagues in the BMT and Cell Therapy division to create technologies to benefit small groups of patients on clinical trials, that can then be expanded to innovative treatments for thousands of people. “We conduct ‘first in human’ clinical trials that teach us how and why a treatment works or doesn’t work,” says Miklos, “and then go back to our colleagues in the laboratory to redesign our approach based on what we learn in those trials.”

“Later, he continues, “pharmaceutical companies may scale up our findings to provide these new, sophisticated treatments to a broader population and to pursue Food and Drug Administration (FDA) approval for these new drugs, such as CAR-T cell treatment.” He notes that the success of Stanford’s cell therapy research is based on the support of all sectors of Stanford Medicine: Stanford Hospital, Lucile Packard Children’s Hospital Stanford, and the Stanford School of Medicine.

Today, the BMT & Cell Therapy division has a revolutionary new cancer treatment called chimeric antigen receptor therapy (CAR-T) that is already approved by the FDA for patients with blood cancers including lymphoblastic leukemia, lymphoma, and multiple myeloma. In February 2016, Stanford treated their first adult patient with CAR-T cell therapy.  In September 2022, Nancy Brandt, 74, became the 500^th adult patient to receive this life-changing treatment. It is anticipated that an additional 250 patients will be treated with CAR-T in 2023.

“A therapy that began in 2016 with one patient on a clinical trial is now being provided to 20 patients a month at Stanford,” notes Miklos. “Seven years ago, we didn’t have any of these treatments available.”

“At the time we started using CAR-T,” adds Miklos, “patients with multiple relapsed chemotherapy refractory lymphoma had very poor prognoses, with an overall 10% one-year survival rate and a median survival of five months. Now, thanks to CAR-T treatment, lymphoma patients have an 80% or more one-year survival rate. Of course, our goal is to make that 100%.”

The human immune system can recognize cells and molecules that don’t belong there, such as cancer tumor cells. In recent years, scientists have discovered how to take advantage of this natural power of the immune system to help fight cancer.

In CAR-T, clinicians remove a patient’s own T cells (the cells that fight infections) and reengineer them in the lab with cutting-edge gene technologies so they can better recognize cancer cells, targeting tumor-specific surface proteins. Then those reconfigured cells are infused back into the patient, where they go to work killing the cancer cells as living, proliferating therapies until all the cancer is eradicated

However, Stanford researchers discovered that sometimes cancer escapes CAR-T therapy because the reengineered T cells stop recognizing the cancer cells. “We realized early on that targeting more than one tumor antigen with CAR-T therapy would be beneficial,” says Miklos.

Stanford researchers led by Mackall have taken CAR-T a step further to address this challenge by modifying the CAR-T treatment so it can target more than one antigen (called CD19 and CD22) either at the same time or sequentially. In fact, Stanford’s CD22-targeted CAR-T therapy is now providing patients whose lymphoma had progressed to greater than 50% long-term remission after CD19-targetted CAR-T.  Because of this significant patient benefit, the FDA has given this treatment a breakthrough designation and is fast tracking the CAR22 drug approval process. Matthew Frank, MD, PhD, assistant professor, BMT and Cell Therapy division, is leading the clinical trial of this CAR22 treatment.

The development of CAR-T therapy was a paradigm shift, enabling clinicians to highjack the patient’s own lymphocytes to kill cancer in a specific and effective way that had never been done before. But some patients are not candidates for this treatment, and they may need a blood and marrow transplant from a histocompatibility-matched donor (also known as a human leukocyte antigen (HLA)-matched donor). This empowers the patient to use the donor’s entire immune system to eliminate their blood cancer and regrow effective immune systems.

Though BMT therapy can be very effective, it comes with a risk of graft versus host disease (GVHD), a serious condition in which the donor’s immune cells that eliminate cancer can sometimes damage the patient’s normal tissues causing skin rash, liver damage and gut inflammation with diarrhea. Miklos refers to this undesirable immune damage as “a civil war between the donor’s and the recipient’s lymphocytes.” BMT division researchers Robert Negrin, MD and Everett Meyer, MD have reduced GVHD risk by engineering the donor graft content to include specialized regulatory T cells that prevent the condition. The benefits of engineered grafts are now being tested in randomized controlled trials for FDA approval to benefit all patients.

But even with improved strategies for preventing GVHD, finding a BMT donor match can be a difficult process.

Among the cancer survivors in attendance at the Stanford reunion earlier this month was Santa Clara County Deputy District Attorney Charlie Huang. He served as Santa Clara County’s prosecutor for 20 years until 2019, when he developed leukemia. Huang’s cancer relapsed, and he underwent an allogeneic (from a donor) blood and marrow transplant from his brother, Denny. Huang overcame the challenges of his transplant but wanted to do something to increase the BMT donor pool so more patients could have access to this treatment option.

With the help of California State Assemblymember Evan Low, Stanford Health, the Leukemia and Lymphoma Society, and the National Marrow Donor Program, Huang drafted California Assembly Bill 1800 and marched it through the California Assembly and Senate with broad support. In September 2022, Governor Gavin Newsom signed this bill to authorize what is now called Charlie’s Law, which offers all 18- to 40-year-old Californians renewing their California driver’s licenses the option to be a bone marrow donor by checking a box, much like organ donation.

CAR-T is fast becoming the gold standard for immune therapies for treating blood cancers. Miklos hopes this technology will become available to harness the immune system to treat solid tumors as well, such as breast, brain, lung, pancreatic and others. One tumor-specific antigen called GD2 is associated with pediatric brain tumors. Mackall and colleagues Robbie Majzner, MD, assistant professor, pediatrics hematology-oncology, and Michelle Monje, MD, PhD, professor, neurology and neurological sciences, have developed an anti-GD2 CAR-T that shows promise in early clinical trials to safely treat brain cancer in children. Similarly, Mackall’s lab has developed an H7B3 CAR-T therapy being tested in adult patients with glioblastoma multiforme (GBM), the most common primary brain tumor in adults, in another cell therapy trial led by Reena Thomas, MD, PhD, clinical associate professor, neurology and neurological sciences.

And as for finding a “cure” for cancer, Miklos notes that the only way to really measure if cancer is “cured” is time. “Remission is the first stage, where we have no evidence of cancer in a patient after 28 days of treatment with CAR-T. But when is it cured? That will be seen over the next five or 10 years, as patients come back for more reunions at Stanford, with their kids, cancer free.”