The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current findings include immunotherapy advances for AML, liver cancer, HPV-related cancers and other solid tumors, biomarkers of response to TIL therapy in melanoma, a greater understanding of the cells regulating skin wound repair, and data confirming the safety of proton therapy for pediatric brain cancer.
Targeting B7-H3 is a potential immunotherapy approach for high-risk AML
Acute myeloid leukemia (AML) is the most common leukemia in adults and, despite advances in targeted therapies, is associated with poor prognoses. Immunotherapy has shown promise, especially in combination with chemotherapy. A research team led by V. Lokesh Battula, Ph.D., demonstrated that the immune checkpoint protein B7-H3 may serve as a potential immunotherapy target in patients with AML. The team found elevated expression of B7-H3 to be associated with poor treatment outcomes in patients with AML. In preclinical studies, researchers demonstrated that blocking B7-H3 with a novel monoclonal antibody enhanced natural killer (NK) cell-mediated killing of AML cells. Additionally, treatment with the monoclonal antibody and human NK cells increased survival in patient-derived xenograft models. These results suggest that targeting B7-H3 may be a therapeutic strategy for high-risk, B7-H3+ AML patients. Next, researchers plan to generate a fully humanized version of the monoclonal antibody for therapeutic applications in AML and B7-H3+ solid tumors. Learn more in Blood.
Perioperative immunotherapy safe and feasible in patients with early-stage liver cancer
Early-stage hepatocellular carcincoma (HCC) — the most common form of liver cancer — has high rates of recurrence following surgery, but there is no approved standard-of-care for pre- or post-surgical treatment. Immunotherapy has improved outcomes in some patients with advanced HCC, but it has not been evaluated in earlier disease stages. Ahmed Kaseb, M.D., and Padmanee Sharma, M.D., Ph.D., led a Phase II trial to evaluate the safety and feasibility of checkpoint blockade as a perioperative (neoadjuvant plus adjuvant) therapy for early-stage HCC. Twenty-seven patients were randomized to receive either nivolumab alone or nivolumab plus ipilimumab. Both single-agent and combination therapy were safe and well-tolerated. Of the patients who completed surgery, 30% had a major pathological response (at least 70% of resected tumor was necrotic), and 25% had a complete pathological response. None of those patients experienced a recurrence after two years. The researchers also identified features of the immune microenvironment correlated with response. Based on these findings, the researchers have planned a national study, led by MD Anderson, of neoadjuvant immunotherapy in operable HCC. Learn more in The Lancet Gastroenterology & Hepatology.
Study targets immunosuppressive receptor to overcome resistance in advanced cancers
While immune checkpoint inhibitors have transformed the treatment and overall survival of several cancers, including melanoma and non-small cell lung cancer, many cancers remain unresponsive to existing checkpoint inhibitors or develop resistance during treatment. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor expressed on immune cells that has been shown to regulate T cell exhaustion and inhibit antitumor immune responses with programmed cell death-1 (PD-1), making it an attractive therapeutic target for overcoming resistance and improving patient outcomes. In a Phase I/II trial led by David Hong, M.D., researchers studied LAG-3 inhibitor ieramilimab (LAG525) and PD-1 antibody spartalizumab in patients with advanced/metastatic solid tumors. In the trial, ieramilimab was well tolerated both as monotherapy and in combination with spartalizumab. Although the combination therapy demonstrated modest antitumor activity, data suggest that targeting LAG-3 may contribute to anti-PD-1 activity in different cancers and should be investigated in combination with other immunotherapies. Learn more in Journal for ImmunoTherapy of Cancer.
ISA101 plus nivolumab shows durable responses in HPV-16+ cancer
ISA101 is a human papillomavirus (HPV) vaccine that uses E6 and E7 synthetic long peptides to activate an immune response against HPV-16, which can cause several types of cancer. The vaccine has been shown to clear HPV-16+ pre-malignant vulvar lesions, but it has limited effect against advanced cancer. This study, led by Michael Curran, Ph.D., and Bonnie Glisson, M.D., reports the long-term outcomes and immune correlates of response from a single-arm clinical trial combining ISA101 and the checkpoint inhibitor nivolumab in 24 patients with advanced HPV-16+ cancers. After a median of 46.5 months, the median duration of response was 11.2 months, median overall survival was 15.3 months and three-year overall survival was 12.5%. Activation of PD-1+ T cells and macrophages in the tumor, as well as immune and inflammatory responses, all were strongly correlated with clinical response. A randomized Phase II clinical trial is underway to follow up on the results. Learn more in the Journal of Immunotherapy for Cancer.
Gene expression patterns correlate with responses to TIL therapy in melanoma
Tumor infiltrating lymphocytes (TILs) are a form of adoptive cell therapy that use immune cells isolated directly from a tumor. In clinical studies, TILs have achieved a response rate of 40-50% in patients with metastatic melanoma, but it is unclear what factors contribute to varied responses between patients. In a study led by Caitlin Creasy, Ph.D., and Chantale Bernatchez, Ph.D., researchers sequenced DNA and RNA from melanoma tumors used to generate TIL therapies to identify characteristics associated with patient outcomes. The rate of gene mutations and corresponding mutant proteins (neoantigens) did not correlate with therapy response or progression-free survival (PFS). However, high expression of the genes PDE1C, RTKN2 and NGFR were associated with response to therapy as well as improved PFS and overall survival (OS), while ELFN1 expression was inversely correlated with patient outcomes. Several of these genes are primarily expressed by cells other than tumor cells, suggesting that the tumor microenvironment plays an important role in determining responses to TIL therapy. Learn more in Clinical Cancer Research.
Study identifies critical cells and mechanisms regulating skin wound repair
Since skin wound repair is an essential biological process to maintain the integrity of healthy skin and protect against infection, understanding factors that promote or prevent wound healing can have significant health implications. Dermal fibroblasts are the main cell type in skin connective tissue, and a specific subgroup called αSMA+ myofibroblasts is associated with wound repair. Kathleen McAndrews, Ph.D., Yejing Ge, Ph.D., Raghu Kalluri, M.D., Ph.D., and colleagues developed new mouse models to show that loss of αSMA+ myofibroblasts leads to dramatic wound-healing defects. Loss of other types of dermal fibroblasts did not result in such profound defects, suggesting αSMA+ myofibroblasts are the critical cell type for this process. The researchers demonstrated the cell surface protein β1 integrin from αSMA+ myofibroblasts is essential for the wound repair process. This study provides important insights into the previously unknown role of αSMA+ myofibroblasts in wound repair, with possible implications for treating chronic non-healing wounds. Learn more in The EMBO Journal.
Low incidence of symptomatic brainstem injury in pediatric patients after proton therapy
Symptomatic brainstem injury (SBI) is a rare but harmful complication following proton beam therapy that can affect neurological and bodily functions dependent on the brainstem. A research team led by Rituraj Upadhyay, M.D. and Arnold dela Cruz Paulino, M.D., assessed the incidence of SBI after proton therapy in 468 children diagnosed with either a medulloblastoma, glioma, ependymoma or atypical teratoid rhabdoid (ATRT) brain tumor. The findings indicate SBI was seen in 3.2 % of pediatric brain tumor patients, with a higher risk attributed to females three years of age and under. Researchers also found that ATRT patients who underwent an autologous stem cell transplant were considered high risk for SBI, and strict radiation dose constraints to the brainstem initiated in 2014 reduced patients’ risk for developing SBI. The findings confirm there is a low incidence of SBI after proton therapy for pediatric brain tumors, and this type of treatment can be a safe option for patients. Learn more in Neuro-Oncology.
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