Research Highlights from the University of Texas MD Anderson Cancer Center provide an insight into recently published studies in fundamental, translational, and clinical cancer research by MD Anderson experts. Current findings include advances in immunotherapy for AML, liver cancer, HPV-related cancers and other solid tumors, biomarkers for response to TIL therapy in melanoma, better understanding of the cells that regulate skin wound repair, and data who confirm the safety of proton therapy in pediatric brain tumor.
B7-H3 targeting is a potential immunotherapy approach for high-risk AML
Acute myeloid leukemia (AML) is the most common leukemia in adults and is associated with poor prognosis despite advances in targeted therapies. Immunotherapy has shown promise, especially when combined with chemotherapy. A research team led by V. Lokesh Battula, Ph.D., showed that the immune checkpoint protein B7-H3 can serve as a potential immunotherapy target in patients with AML. The team found that increased expression of B7-H3 is associated with poor patient outcomes in patients with AML. In preclinical studies, researchers showed that blocking B7-H3 with a novel monoclonal antibody enhanced natural killer (NK)-mediated killing of AML cells. In addition, treatment with the monoclonal antibody and human NK cells increased survival in patient-derived xenograft models. These results suggest that targeting B7-H3 could be a therapeutic strategy for high-risk B7-H3+ AML patients. Next, researchers plan to produce a fully humanized version of the monoclonal antibody for therapeutic applications in AML and B7-H3+ solid tumors. Find out 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 a high rate of recurrence after surgery, but there is no approved standard of care for pre- or postoperative management. Immunotherapy has improved outcomes in some patients with advanced HCC, but has not been studied at earlier stages of the disease. Ahmed Kaseb, MD, and Padmanee Sharma, MD, Ph.D., directed a Phase II study evaluating 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 monotherapy and combination therapy were safe and well tolerated. Of the patients who completed surgery, 30% had a significant pathologic response (at least 70% of the resected tumor was necrotic) and 25% had a complete pathologic response. None of these patients had a recurrence after two years. The researchers also identified features of the immune microenvironment that correlate with the response. Based on these findings, researchers led by MD Anderson planned a national trial of neoadjuvant immunotherapy in operable HCC. Find out more in The Lancet Gastroenterology & Hepatology.
Study targets immunosuppressive receptor to overcome resistance in advanced cancer
While immune checkpoint inhibitors have transformed the treatment and overall survival of several cancers, including melanoma and non-small cell lung cancer, many cancers are unresponsive to existing checkpoint inhibitors or develop resistance during treatment. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor expressed on immune cells and has been shown to regulate T cell exhaustion and inhibit antitumor programmed cell death-1 (PD-1) immune responses, making it an attractive therapeutic target Goal makes to overcome resistance and improve treatment outcomes. In one of Dr. In a phase I/II study led by David Hong, researchers evaluated the LAG-3 inhibitor ieramilimab (LAG525) and the PD-1 antibody spartalizumab in patients with advanced/metastatic solid tumors. In the study, leramilimab was well tolerated both as monotherapy and in combination with spartalizumab. Although the combination therapy demonstrated modest antitumor activity, the data suggest that targeting LAG-3 may contribute to anti-PD-1 activity in various cancers and should be explored in combination with other immunotherapies. Find out more in Journal of Cancer Immunotherapy.
ISA101 plus nivolumab demonstrates durable responses in HPV 16+ cancer
ISA101 is a human papillomavirus (HPV) vaccine that uses synthetic long peptides E6 and E7 to induce an immune response against HPV-16, which can cause various types of cancer. The vaccine has been shown to cure HPV 16+ pre-malignant vulvar lesions but has limited efficacy against advanced cancer. This study, led by Michael Curran, Ph.D., and Bonnie Glisson, MD, 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 became -16+ cancer. After a median of 46.5 months, the median duration of response was 11.2 months, the median overall survival was 15.3 months, and the 3-year overall survival was 12.5%. Activation of PD-1+ T cells and macrophages in the tumor, as well as immune and inflammatory responses, were all strongly correlated with the clinical response. A phase II randomized clinical trial is underway to follow up the results. Find out more in Journal of Immunotherapy in Cancer.
Gene expression patterns correlate with response to TIL therapy in melanoma
Tumor infiltrating lymphocytes (TILs) are a form of adoptive cell therapy that uses immune cells isolated directly from a tumor. In clinical trials, TILs have achieved a 40-50% response rate in patients with metastatic melanoma, but it is unclear what factors contribute to differential patient responses. 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 features associated with the related to patient outcomes. The rate of gene mutations and corresponding mutated proteins (neoantigens) did not correlate with response to therapy or progression-free survival (PFS). However, high expression of the genes PDE1C, RTKN2 and NGFR were associated with response to therapy and improved PFS and overall survival (OS), while ELFN1 Expression was inversely correlated with patient outcomes. Some of these genes are mainly expressed by cells other than tumor cells, suggesting that the tumor microenvironment plays an important role in determining response to TIL therapy. Find out more in Clinical Cancer Research.
The study identifies critical cells and mechanisms that regulate skin wound healing
Because 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 are a specific subgroup called αSMA+ Myofibroblast is associated with wound healing. Kathleen McAndrews, Ph.D., Yejing Ge, Ph.D., Raghu Kalluri, MD, Ph.D., and colleagues developed new mouse models to show this loss of αSMA+ Myofibroblasts lead to dramatic wound healing disorders. The 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. Researchers demonstrated the cell surface protein β1 integrin from αSMA+ Myofibroblasts is essential for the wound healing process. This study provides important insights into the previously unknown role of αSMA+ Myofibroblasts in wound healing, with potential implications for the management of chronic non-healing wounds. Find out more in The EMBO Journal.
Low incidence of symptomatic brainstem injuries in pediatric patients after proton therapy
Symptomatic brainstem injury (SBI) is a rare but detrimental complication after proton beam therapy that can impair brainstem-dependent neurological and physical functions. A research team led by Rituraj Upadhyay, MD, and Arnold dela Cruz Paulino, MD.investigated the incidence of SBI after proton therapy in 468 children diagnosed with either medulloblastoma, glioma, ependymoma, or an atypical teratoid rhabdoid (ATRT) brain tumor. The results show that SBI was observed in 3.2% of pediatric brain cancer patients, with a higher risk attributed to women under the age of three. Researchers also found that ATRT patients undergoing autologous stem cell transplants were considered at high risk for SBI, and strict brainstem radiation dose limits, introduced in 2014, reduced patients’ risk of developing SBI. The results confirm that there is a low incidence of SBI after proton therapy in pediatric brain tumors and this type of treatment may be a safe option for patients. Find out more in neuro-oncology.
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About MD Anderson
The MD Anderson Cancer Center at the University of Texas at Houston is recognized as one of the world’s most respected centers focused on the care, research, education and prevention of cancer patients. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked #1 for cancer in US News & World Report’s “Best Hospitals” ranking. Since the rankings began in 1990, it has been named one of the top two hospitals for cancer in the country. MD Anderson is a recipient of a Cancer Center Grant from the National Institutes of Health NCI (P30 CA016672).
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