City of Hope doctors present research on new immunotherapies at American Society of Hematology conferenceDecember 9, 2019
Researchers also reveal a first-of-its-kind study on long-term health outcomes for bone marrow transplant survivors
DUARTE, Calif. — City of Hope physicians and researchers at the American Society of Hematology (ASH) meeting in Orlando presented research on novel chimeric antigen receptor (CAR) T therapy and other potential new therapies for blood cancers, as well as a comprehensive report on long-term health problems bone marrow transplant (BMT) survivors face and prevention efforts that can be taken.
“City of Hope continues to be at the forefront of finding new treatments and pursuing innovative research for blood cancers and other hematological malignancies,” said Eileen Smith, M.D., chair of City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation and the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation. “Our clinical and laboratory researchers are dedicated to finding more effective CAR T cell therapies and other immunotherapies, and our survivorship studies on BMT patients seek to improve long-term health outcomes for these survivors.”
City of Hope physicians and scientists discussed clinical trials that provide the foundation for new treatments for patients with leukemia, lymphoma and multiple myeloma. They also discussed preclinical studies on a new target for acute myeloid leukemia.
There are currently 200,000 BMT survivors and that number is expected to increase to exceed half a million over the next decade. BMTs can cure blood cancer patients but there are short-term and long-term health complications that patients and their health care providers need to be aware of so they can also try to prevent these complications.
“Many of our BMT patients will live for many decades after their transplant so our goal is to understand what happens to them, educate them about potential short-term and long-term risks and what can be done to prevent some of these health conditions,” said Saro Armenian, D.O., M.P.H., City of Hope associate professor in the departments of Pediatrics and Population Sciences and director of the Center for Survivorship and Outcomes within the Hematologic Malignancies Research Institute. “Some of these conditions are preventable. For instance, there are early screenings for some cancers. If someone is at a high risk of developing cardiovascular disease, that is a condition you can pick up early and help prevent before it becomes a life-threatening condition.”
Led by Armenian, a first-of-its-kind study took a closer look at this issue. The study examined long-term health outcomes for nearly 1,200 acute myeloid leukemia BMT survivors (the majority were allogenic transplants) compared with nearly 1,200 siblings over a 40-year span. The patients had received transplants at City of Hope, University of Alabama, Birmingham and University of Minnesota.
Approximately 66% of survivors (compared with 30% of their siblings) developed a severe or life-threatening chronic condition 20 years after BMT. The most common conditions were different types of cancers, diabetes, blood clots, cataracts and major joint replacement.
Overall, survivors had a three-fold increased risk of developing a severe health condition compared with their siblings. They were 10 times more likely to develop a different type of cancer such as skin, breast, colon and prostate; these are cancers that are amenable to early screening and prevention. Furthermore, BMT survivors were five times more likely to develop diabetes, and four times more likely to develop a life-threatening blood clot, compared to their siblings.
“It is important to recognize that the benefit of the transplant in terms of curing a patient far outweighs the potential harms that are down the line,” Armenian said. “It’s our moral imperative to not only get them through the transplant but to care for them well beyond that into old age.”
“What we tell our BMT patients is you’ve made it through the transplant and now it’s time for you to take ownership over your own health and well-being,” Armenian said. “That may be an optimal time when patients are actually engaged to think about the next chapter of their lives and how they’re going to optimize their health.”
More effective treatments with fewer side effects are needed for patients with relapsed/refractory non-Hodgkin lymphoma (NHL). Options are particularly limited for those with B cell NHL or who have relapsed or not responded after CAR T cell therapies.
For those reasons, researchers at City of Hope and other institutions are looking for new options and one might be immunotherapy. Mosunetuzumab is a bispecific antibody targeting both CD3 (a protein found on the surface on T cells) and CD20 on the surface of B cells. The therapy redirects T cells to engage and eliminate malignant B cells.
Previous studies have demonstrated that mosunetuzumab had promising efficacy and favorable tolerability. An expanded Phase 1 multicenter trial examined dose escalation of mosunetuzumab.
Elizabeth Budde, M.D., Ph.D., assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, was the study’s senior. The study reveals results from Group B, in which mosunetuzumab was administered with increased dosing on the first, eighth and 15th day of the first cycle and then as a fixed dose on the first day of each subsequent 21-day cycle.
Approximately 270 patients in Group B were part of the trial. Among efficacy-evaluable patients across all dose levels, overall response rates (ORR) and complete response (CR) rates were 62.7% (42/67) and 43.3% (29/67) in indolent NHL patients, 37.4% ORR (46/124) and nearly 19.5% (24/124) of aggressive NHL patients.
CRs also appeared durable with 82.8% (24/29) of indolent NHL patients in remission after 26 months, and 70.8% (17/24) of aggressive NHL patients were in CR after nearly 16 months.
Side effects were minimal. They included cytokine release syndrome, which occurred in 29% of patients and was mostly low grade (27.9%) with only 1.1% grade 3. Neurological complications occurred in 43.7% of patients: 40% had low-grade problems such as headache, insomnia and dizziness and 3.7% had grade 3. Researchers noted that the frequency of cytokine release syndrome and neurological complications did not correlate with mosunetuzumab exposure, likely due to step-up dosing, which effectively mitigated acute toxicities and allows administration of higher doses.
Researchers concluded that mosunetuzumab had favorable tolerability and durable efficacy in patients with heavily pre-treated relapsed/refractory B cell NHL and achieved complete responses in patients whose disease progressed after CAR T therapies.
“As clinicians, we are always in search of new treatments for patients who have few therapeutic options,” Budde said. “Mosunetuzumab, which has also demonstrated few serious side effects and encouraging durable therapeutic efficacy, could be a step in that direction.”
A potential new CAR T cell therapy for patients with chronic lymphocytic leukemia works well with few side effects
Oral targeted therapies have improved treatment outcomes for patients with chronic lymphocytic leukemia, an incurable cancer. But some patients may not respond to those drugs, and they are in need of other treatment options.
Lisocabatagene Maraleucel (liso-cel), a Juno CAR T therapy, may be the answer. Updated results from a phase 1 clinical trial of liso-cel for patients who had taken ibrutinib unsuccessfully and had failed two or three lines of therapy for chronic lymphocytic leukemia were presented at ASH by Tanya Siddiqi, M.D., director of City of Hope’s Chronic Lymphocytic Leukemia Program. A number of these patients had progressed after both ibrutinib and venetoclax therapy.
Of 23 patients evaluated for the therapy’s safety, very few had high grade serious toxicities such as cytokine release syndrome and neurotoxicity.
“Specifically, when you talk about CAR T therapy, you talk about these toxicities being the most common but so far, two had grade 3 cytokine release syndrome and nobody had grade 4 or 5,” Siddiqi said. “As far as neurotoxicity is concerned, five patients had grade 3 or 4 neurotoxicity and none had grade 5.”
More common side effects included low grade cytokine release syndrome (fever and chills) that is easily manageable.
As early as 30 days after receiving liso-cel, about 75% of 20 patients evaluated for the therapy’s efficacy had undetectable minimal residual disease (MRD) in the blood and 65% in the marrow, that is no detectable traces of cancer in a patient’s blood or bone marrow. Majority of patients achieved an early objective response (cancer diminished or disappeared) to liso-cel at the 30 day response assessment. Over time, liso-cel has also demonstrated deep and durable remissions in most patients, or a remission that endures over time.
“It’s been almost two years since the first few patients received liso-cel on this trial and at least three or four of them are still in excellent remission with no recurrent MRD, while later patients are still in follow-up at under two years” Siddiqi said. “The results for this trial are very encouraging as liso-cel has so far demonstrated to be highly effective with few serious side effects in patients with fairly refractory CLL.”
Liso-cel is now being tested in the phase 2 portion of this trial, which is a continuation of this trial and is also taking place at City of Hope.
Trial examined PET-adapted nivolumab or nivolumab plus chemotherapy as a bridge to transplant in relapsed/refractory Hodgkin lymphoma
The standard treatment for patients with relapsed/refractory Hodgkin lymphoma is second-line chemotherapy followed by a stem cell autologous transplant. A multicenter trial, led by City of Hope’s Alex Herrera, M.D., instead used a sequential immunotherapy first-line approach to treat the cancer. The immunotherapy used was nivolumab, which works by blocking the PD-1 immune checkpoint pathway that tumors often hijack to evade the immune system.
In previous trials also led by Herrera, assistant professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, nivolumab and brentuximab vedotin — an antibody-based treatment that targets delivery of chemotherapy only to Hodgkin lymphoma cells — have been effective against relapsed/refractory Hodgkin lymphoma. This trial evaluates whether nivolumab alone can be powerful enough to get a patient into remission without the need for chemotherapy prior to a transplant.
For the trial, 43 patients received nivolumab every two weeks for up to six cycles. A PET-CT scan was performed on patients after the third and sixth cycle to assess whether the cancer had responded to treatment. Patients who were not in remission after six cycles of nivolumab then received nivolumab/ICE (NICE), a standard chemotherapy regime for these patients.
For patients who received nivolumab alone, the overall response rate (ORR, or cancer diminished or disappeared) was 78% and the complete response rate (CR, or cancer disappeared) was 70%. Seven patients treated with NICE had a 100% response rate. Among 35 evaluable patients, the ORR was 94% and CR was 91%.
A year after starting the trial, 79% of all patients remained in remission. Twenty-seven patients were also able to receive an autologous transplant directly after the trial. Nivolumab’s side effects were mild. They included fatigue (28%), rash (18%), and fever (15%). Patients who also received NICE experienced nausea (71%), vomiting (57%), anemia (43%) and fatigue (43%).
The study concluded that PET-adapted nivolumab/NICE in patients was found to be well-tolerated and effective as a second-line therapy. Using nivolumab alone was also an effective bridge to transplant in a majority of patients, sparring them the toxicity of traditional high-dose chemotherapy. Patients who did not achieve CR with nivolumab alone responded to nivolumab/NICE.
“The results of the study are really exciting,” Herrera said. “We demonstrated you can use immunotherapy alone to safely and effectively treat relapsed/refractory Hodgkin lymphoma and is also a bridge to transplant. We can spare patients from receiving chemotherapy. In the future, we’ll continue to evaluate immunotherapy approaches to treat relapsed/refractory Hodgkin lymphoma.”
Next steps include a trial to establish the role of immunotherapy as a second-line therapy prior to transplant.
Matthew Mei, M.D., assistant clinical professor with City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, presented this study at the ASH conference.
Multiple myeloma patients whose disease has returned, or is no longer responding to current therapies, are in need of new treatments that are effective and cause few serious side effects. TAK-079, a Takeda immunotherapy drug that is delivered as a subcutaneous injection and targets the CD38 protein expressed by myeloma cells, could be such a therapy.
For the multicenter trial led by Amrita Krishnan, M.D., director of City of Hope’s Judy and Bernard Briskin Center for Multiple Myeloma Research and professor in its Department of Hematology & Hematopoietic Cell Transplantation, 31 patients, who had received at least three other therapies and previous exposure to other specific treatment, were enrolled in four-dose cohorts. They received an initial dose of 135 milligrams and are currently receiving 1,200 milligrams.
After the four-dose levels were tested, 43% of 28 patients (for which data is available) had an objective response rate (cancer had diminished or disappeared) and experienced few side effects. Only 4% of patients had drug-related infections and 11% had drug-related anemia.
“TAK-079 is well-tolerated by patients and they have been able to stay on it,” Krishnan said. “Because TAK-079 is so easy to administer as an injection, there is also a potential for patients to use this at home.”
Fat mass and obesity-associated (FTO) protein is highly expressed on acute myeloid leukemia (AML) cells, making it a promising target in leukemia treatment. But currently, there are few drugs targeting the FTO protein in treating leukemia.
Under supervision of Jianjun Chen, Ph.D., of the Simms/Mann Family Foundation Chair in Systems Biology, Rui Su, Ph.D., and her colleagues have identified two small-molecule compounds (CS1 and CS2) targeting FTO protein specifically and effectively with measurements showing a high potency of the compounds. Via RNA sequencing, researchers found that CS1 and CS2 exert their anti-leukemic effects through the FTO-associated signaling pathway.
Through bioluminescence imaging, researchers also found that treatment with either CS1 or CS2 suppressed leukemia progression and prolonged survival in ‘human-in-mouse’ xenograft and patient-derived AML PDX models.
Next steps for the research include starting a clinical trial for patients using the CS1 and CS2 compounds to target the FTO protein.
Research uncovers different role for CD25 in some acute lymphoblastic lymphomas and presents a novel target for therapies
A team of researchers led by City of Hope’s Jaewoong Lee, Ph.D., assistant research professor in the Department of Systems Biology, recently sought to understand why, when reviewing data from nearly 140 clinical trials for cancer patients, they saw that a protein called CD25 appears to be one of the strongest predictors of poor clinical outcome in patients with B cell malignancies like lymphoma, but not in other cancer types. It was particularly curious because CD25 is part of a receptor (IL2) that typically promotes the growth of T cells, used by the body to fight infections.
The team’s experiments using genetic mouse models and engineered patient-derived B cell leukemia and lymphoma tissue grafts revealed a surprising function of CD25 that is independent of IL2 in B cells and B cell derived leukemia and lymphoma.
“We were able to identify that CD25 plays a role as a previously unrecognized feedback regulator of tumor-causing B cell receptor signaling, which provides a proliferative advantage to malignant B cells and also acts as a biomarker and predictor of poor clinical outcomes,” Lee said.
For adults with a rare subtype of the most common childhood cancer, acute lymphoblastic leukemia (ALL), called Ph-Positive ALL, as well as children with a similar subtype called Ph-like ALL who have high CD25 expression at the time of diagnosis, the findings provide a rationale for the therapeutic targeting of CD25 in such cancers.
To test that rationale, Lee and the team used patient-derived tissue graft models of drug-resistant B cell malignancies and treated them with a with a CD25-specific antibody drug-conjugate (ADCT-301).
“As a strategy to destroy CD25-expressing B cell malignancies, treatment with ADCT-301 either extended the survival of transplant recipients or eradicated disease,” said Lee of the successful outcome.
Next, the team would like to figure out how CD25 provides a growth advantage for malignant B cells.
“We found several novel partner proteins working with CD25,” Lee added. “So, we will likely test if we can also target novel partner proteins together with CD25 to eliminate malignant B cells.”
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About City of Hope
City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope’s translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is the highest ranked cancer hospital in the West, according to U.S. News & World Report’s Best Hospitals: Specialty Ranking. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.