Novel approaches highlight potential of cell therapy for a wider array of cancers
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The ideal strategy to treat cancer with cell therapy can vary greatly depending on tumor type.
On one hand, outcomes for patients with hematologic malignancies might be improved by modifying current chimeric antigen receptor T-cell therapy constructs.
On the other, the complexity of treating solid tumors may require combination strategies to enhance effectiveness, according to Marcela V. Maus, MD, PhD, director of the cellular immunotherapy program at Mass General Cancer Center, associate professor of medicine at Harvard Medical School and member of the Healio | Cell Therapy Next Peer Perspective Board.
Three presentations at this year’s American Association for Cancer Research Annual Meeting highlighted how distinct approaches may be utilized to enhance the effectiveness of cell therapies for blood cancers or solid tumors.
“All three of these studies show exciting results in different populations using very different kinds of treatments,” Maus said. “These researchers have shown just how much cell therapy can change outcomes for patients with devastating diseases.”
Healio spoke with investigators about the results of these three studies and asked other specialists in the field to offer insights about the potential impact the findings will have on clinical care.
‘Robust’ activity in pediatric brain cancer
Younger patients with diffuse midline glioma experienced prolonged benefit after receiving an investigational GD2-directed CAR T-cell therapy developed at Stanford University.
Updated phase 1 trial results presented showed patients experienced periods of radiographic and clinical improvement after multiple doses.
Diffuse midline glioma is one of the most common forms of pediatric brain cancer. Most patients survive less than a year after diagnosis, according to Michelle Monje, MD, PhD, professor in the department of neurology at Stanford University and investigator at Howard Hughes Medical Institute.
Monje — who helps lead the trial — credited patients who donated biopsy or autopsy specimens for helping to advance knowledge of the disease and make the new treatment possible.
“[This is] an incredibly promising strategy and the only thing I’ve ever seen be robustly effective against this disease,” Monje told Healio. “It truly feels as though we are finally taking steps in the right direction to treat this terrible disease, and I’m hopeful that this approach will ultimately be a very important part of an effective treatment.”
Previous results from the study showed radiographic tumor regressions but a lack of treatment durability, Robbie G. Majzner, MD, assistant professor of pediatrics in the division of hematology and oncology at Stanford University, told Healio.
“We realized that we needed to retreat patients more frequently,” he added.
Originally, researchers planned to wait for disease progression before providing additional doses of the CAR-T, Majzner said. His group’s approach has shifted to providing additional doses at an average of 6 weeks apart (range, 4-8) via intracerebral ventricular administration directly into central nervous system fluid.
The trial also started treating patients at a higher dose level, tripling the initial IV dose to 3 million cells/kg.
The change from IV to intracerebral ventricular admiration is logical, Maus said.
CAR-T typically has been used to treat blood cancers that have spread throughout the body. However, due to the blood-brain barrier, a localized approach likely is required to treat brain tumors, she added.
Maus acknowledged that T cells have been known to cross the blood-brain barrier, but the use of IV administration for brain tumors is inefficient compared with direct injection into the cerebrospinal fluid.
“It likely increases the number of effectors cells that can help kill parts of the tumor,” she said. “It is a very wise strategy that gets a useful dose to where it needs to be.”
Sneha Ramakrishna, MD, an instructor of pediatrics in the division of hematology and oncology at Stanford University, conducted the trial’s correlative analyses. Intracerebroventricular administration exhibited a superior safety profile because it resulted in limited proinflammatory cytokines in peripheral blood, she said.
“Patients were able to tolerate the [intracerebroventricular] dose administrations much better than IV dosing, while still gaining significant clinical benefit from each CAR T-cell administration,” she told Healio. “This is a critical learning point in our trial, and it has informed our thinking about next steps for this therapy.”
No study participants developed high-grade cytokine release syndrome after intracerebroventricular administration of GD2-directed CAR-T.
No dose-limiting toxicities occurred for patients treated at the initial dose level; however, three patients treated at the second dose level experienced dose-limiting toxicity in the form of grade 4 CRS.
Nine of 10 patients evaluable for treatment efficacy showed evidence of radiographic or clinical improvement of symptoms after IV infusion of GD2-directed CAR-T. Two patients showed greater than 95% reduction in tumor volume.
Finding a scientific way to evaluate the success of this therapy is difficult because the volume of tumor regression does not reflect quality-of-life improvements — such as being able to clasp a hand or regain the ability to walk — that don’t appear on scans, Majzner told Healio | Cell Therapy Next. One young girl with debilitating neurologic effects from her tumors zipped across a sidewalk on a scooter after receiving the investigational therapy, he added.
“The infiltrative nature of this disease makes radiographically assessing the response difficult,” Majzner said. “We've integrated patient-reported outcomes into the trial to prospectively gather data about how our patients have improved from a personal perspective.”
Maus concurred, noting that — from a medical oncologist’s perspective — there is no good way to accurately measure brain tumors because of their diffuse nature.
“It is not a solid mass like a breast or lung tumor that we can measure easily with a CT scan,” she said. “The fact that these researchers are seeing a clinical benefit with this GD2-CAR is the most important thing because it not only improved neurologic function, but also the patient’s quality of life.”
‘Encouraging’ benefit in solid tumors
Researchers from Europe are looking for an approach to effectively treat solid tumors with CAR-T by examining the use of an amplifying mRNA vaccine in combination with a novel CAR construct.
Early data from a phase 1/phase 2 dose-escalation trial showed encouraging clinical activity for patients with testicular cancer or ovarian cancer who received the investigational regimen.
The agents used in the trial included BNT211 (BioNTech) — an autologous CAR T-cell therapy that targets the oncofetal antigen Claudin-6 (CLDN6) — and CARVac (BioNTech), a CLDN6-encoding mRNA-based vaccine designed to enhance CAR T-cell activity.
Investigators chose CLDN6 as the CAR-T target because of its absence in adult healthy tissue and high expression in certain cancers, John Haanen, MD, PhD, professor of translational cancer immunotherapy at Leiden University Medical Center and leader of the cancer immunotherapy research group at Netherlands Cancer Institute, said during a presentation.
“CARVac was developed to target antigen-presenting cells in lymphoid tissue after systemic administration,” Haanen said. “[It] drives the expansion and persistence of CAR T cells while enhancing their antitumor activity.”
Haanen and colleagues enrolled 16 heavily pretreated patients (median age, 46 years; range, 23-68; 62.5% male) as part of a multicenter study to evaluate the safety and efficacy of BNT211 alone or in combination with CARVac for patients with relapsed or refractory CLDN6-positive solid tumors. All study participants underwent lymphodepletion prior to infusion with BNT211 regardless of treatment arm.
Median follow-up was 127 days (range, 2-348).
Forty-three percent of patients treated during the study achieved objective response to therapy. Researchers reported an 86% disease control rate among patients who underwent 6-month follow-up evaluation.
Results showed higher ORRs with combination therapy than CAR-T monotherapy.
No patients who received CAR T cells alone at dose level one achieved a response to therapy vs. 33% in the combination arm. Likewise, 33% of patients had a response at dose level two of CAR T cells alone compared with 75% who received both CAR T cells and CARVac.
“We found robust engraftment of CAR T cells in all patients,” Haanen said. “This translated into a very encouraging clinical benefit.”
Seventy percent of patients experienced grade 1 or grade 2 CRS. No patients developed neurotoxicity.
Two patients at dose level two — one who received combination therapy and one who received CAR-T monotherapy — experienced dose-limiting toxicities. Grade 3 or higher treatment-related adverse events more than doubled in dose level two for both treatment arms.
The investigators noted pronounced cytopenia among patients with testicular cancer who recently received high-dose chemotherapy and autologous hematopoietic stem cell transplant.
This prompted researchers to open a new study cohort for these patients that used a reduced lymphodepletion regimen prior to CAR T-cell infusion. This group had an ORR of 80%, with a disease control rate of 100%. One patient in the new cohort achieved complete response to therapy.
“Combining a CAR and mRNA-mediated antigen delivery is a promising approach to rescue CARs that may not encounter enough tumor cells or engage enough antigen on tumor cells to be effective,” Michel Sadelain, MD, PhD, director of Center for Cell Engineering at Memorial Sloan Kettering Cancer Center and member of the Healio | Cell Therapy Next Peer Perspective Board, told Healio.
“The mechanism of action of CARVac, depending on what cell types express the targeted antigen, will be important to determine to maximize efficacy and minimize toxicity,” added Sadelain, who was not involved with the study.
Use of a vaccine in combination with CAR-T is an approach that few groups are actively investigating, Maus said. She described the results from Haanen and colleagues as “innovative and promising.”
“Claudins are becoming a really interesting target for solid tumors and CAR T cells,” Maus said. “This vaccine boosting may produce significant results, but it is too early to know what the true effect of the vaccine was in this study.”
Potential ‘breakthrough’ for relapsed lymphoma
Another emerging cellular therapy uses a different effector cell platform altogether.
Researchers at The University of Texas MD Anderson Cancer Center, along with commercial partners, have combined natural killer (NK) cells with a bispecific antibody for patients with relapsed or refractory CD30-positive lymphoma.
All patients who received the recommended phase 2 dose of the investigational treatment achieved an objective response to therapy.
Investigators based a phase 1/phase 2 study’s approach on extensive preclinical work in the lab of Katy Rezvani, MD, PhD, director of translational research in the department of stem cell transplantation and cellular therapy at MD Anderson.
Rezvani’s lab found that NK cells preactivated with cytokines, expanded and precomplexed with AFM13 (Affimed) — an investigational bispecific antibody — induced greater response rates in preclinical mouse models than either preactivated NK cells or AFM13 alone.
“We hypothesized that combining a bispecific molecule with cord blood-derived NK cells would induce CAR-like NK cells that are more active than conventional NK cells and persist within the body for a longer amount of time,” Yago L. Nieto, MD, PhD, professor in the department of stem cell transplantation and cellular therapy at MD Anderson, told Healio.
AFM13 binds to CD16A on the surface of NK cells and CD30, an antigen present in all Hodgkin lymphoma cells and a sizable proportion of T-cell lymphomas, Nieto said.
The AFM13 molecule is bound to donor-derived NK cells at MD Anderson’s good manufacturing practice facility in an incubation process called “precomplexing.” This causes the final cell therapy product to “act like a magnet” that identifies and binds to CD30-positive lymphoma cells, Nieto added.
The single-center study included 22 heavily pretreated patients (mean age, 40 years; range, 20-70; 68% male) with relapsed or refractory CD30-postive lymphomas. Study participants received lymphodepleting chemotherapy, followed by two cycles of AFM13-NK cell infusions a median 56 days apart, in addition to weekly doses of AFM13 after the cellular therapy infusions.
Median follow up was 9 months (range, 1-19).
Seventeen of 19 patients achieved metabolic response to therapy, equating to an overall response rate of 89.5%. Ten patients achieved complete response to therapy.
All 13 patients who received the recommended phase 2 dose had metabolic response to the regimen. Eight achieved complete responses and five achieved partial responses.
Investigators reported a 52% EFS rate and an 81% OS rate across all dose levels.
Safety analysis showed no cases of CRS, immune effector cell-associated neurotoxicity syndrome or graft-versus-host disease. Researchers observed no dose-limiting toxicities, and they established the recommended phase 2 dose at 108 NK cells/kg.
“All patients who received the recommended phase 2 dose responded to therapy, with nearly two-thirds of them achieving a complete response,” Nieto said. “That level of activity is remarkable in this patient population.”
Henry Chi Hang Fung, MD, FACP, FRCPE, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, agreed with Nieto’s assessment. He called the 9-month response and survival results “very impressive.”
“Treatment options are very limited for this group of patients,” he told Healio. “This could potentially be a breakthrough treatment for patients with relapsed or refractory CD30-positive lymphomas.”
One size does not fit all
The treatments highlighted at AACR utilize unique methods to treat different malignancies.
However, they all employ creative and daring approaches to treat patients with limited therapeutic options, Maus said.
She pointed to the “heroic efforts” researchers at Stanford are taking to treat younger patients with diffuse midline glioma, which requires investigators to navigate “a narrow window between dealing with the toxicities and maintaining anti-tumor effect.”
Results from the group in Europe using a CLDN6-directed CAR-T plus vaccine offers hope that cell therapy has a future in the treatment of solid tumors, Maus said.
“Some people have the idea that applying CARs to solid tumors is proving to be an ineffective strategy,” she said. “A study like this one provides evidence that it's starting to work.”
The precomplexed NK cell-bispecific combination that Nieto and colleagues used is intriguing because the use of immune effector cells beyond the T cell may prove to have superior anti-tumor capabilities with fewer treatment-related toxicities, Maus said. More studies using these cells are needed to determine their value as cancer treatments, she added.
“I am really excited about all three of these approaches,” Maus said. “There are enough different kinds of cancer that I think all these therapeutics and the science behind them have the potential to positively impact patients who need them.”
For more information:
Henry Chi Hang Fung, MD, FACP, FRCPE, can be reached at henry.fung@tuhs.temple.edu.
John Haanen, MD, PhD, can be reached at j.haanen@nki.nl.
Robbie G. Majzner, MD, can be reached at rmajzner@stanford.edu.
Marcela V. Maus, MD, PhD, can be reached at mvmaus@mgh.harvard.edu.
Michelle Monje, MD, PhD, can be reached at mmonje@stanford.edu.
Yago L. Nieto, MD, PhD, can be reached at ynieto@mdanderson.org.
Sneha Ramakrishna, MD, can be reached at ramakrs@stanford.edu.
Michel Sadelain, MD, PhD, can be reached at m-sadelain@ski.mskcc.org.
References:
The following were presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans:
Haanen J, et al. Abstract CT002.
Majzner RG, et al. Abstract CT001.
Nieto YL, et al. Abstract CT003.
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