image: Cancer cells
Credit: MD Anderson Cancer Center
HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.
Novel allogeneic NK cell therapy from induced pluripotent stem cells shows encouraging efficacy in relapsed or refractory B-cell lymphoma patients
Patients with relapsed or refractory B-cell lymphomas have limited treatment options, although new immune and cell therapies are being developed. Natural killer (NK) cells derived from induced pluripotent stem cells (iPSC) or cord blood are a novel source for cancer cell therapies. In a new Phase I trial, Paolo Strati, M.D., and colleagues evaluated the safety and efficacy of FT596 – a novel allogenic iPSC-derived chimeric antigen receptor (CAR) NK cell therapy – as a monotherapy and in combination with rituximab in 86 patients with relapsed or refractory B-cell lymphomas. The cells were enhanced with three antitumor approaches, including a CD19-targeted CAR, a modified CD16 receptor and an interleukin-15 receptor fusion protein. According to this first-in-human trial, both regimens were well tolerated, and patients with both indolent and aggressive transformed B-cell lymphomas achieved deep and durable responses. Fewer than 15% of patients experienced low-grade cytokine release syndrome, and no neurotoxicity was observed, suggesting the cell therapy was safe for this patient population. Learn more in The Lancet.
Targeted therapies show responses in pretreated HER2-mutant metastatic breast cancer
The HER2 protein helps cells grow and divide, but it can lead to cancers in the breast, stomach and colon when it acts abnormally. While existing treatments target excessive HER2 activity, they haven’t been widely tested in cases with specific HER2 mutations. In a Phase II trial, Paula Pohlmann, M.D., Ph.D., and colleagues evaluated two HER2-targeted therapies, tucatinib and trastuzumab, in 31 women with advanced breast cancer. These women had metastatic HER2-negative breast cancer harboring specific HER2 mutations and had already undergone other treatments. The results showed that 42% of patients experienced tumor reduction with these targeted therapies. On average, their cancer remained controlled for about 9.5 months, with treatment benefits lasting around 12.6 months. These findings suggest tucatinib and trastuzumab may offer a treatment option for these patients and support further research to confirm their broader potential. Learn more in Nature Medicine.
Triplet combination is safe, shows promise for advanced clear cell renal cell carcinoma
The tyrosine kinase inhibitor (TKI) sitravatinib has shown antitumor responses and demonstrated an increase in effectiveness when used in combination with immune checkpoint inhibitors to treat patients with advanced clear cell renal cell carcinoma (ccRCC). In a Phase I trial, researchers led by Pavlos Msaouel, M.D., Ph.D., Linghua Wang M.D., Ph.D., and Jianjun Gao, M.D., Ph.D., examined the safety and efficacy of a triplet combination of sitravatinib, nivolumab and ipilimumab in 22 previously untreated patients with advanced ccRCC. The trial established a safe dose that resulted in a 45.5% objective response rate, an 86.4% disease control rate and a median progression-free survival of 14.5 months. Using single-cell RNA sequencing, the researchers also identified tumor cell-specific gene signatures that predicted treatment resistance and clinical outcomes. These results offer important insights to improve therapeutic strategies for patients with ccRCC. Learn more in Nature Communications.
Treatment efficacy for KRAS G12C-mutated lung cancer varies with co-mutations
Non-small cell lung cancers (NSCLCs) harboring KRAS G12C mutations are notoriously difficult to treat. While KRAS G12C inhibitors, such as adagrasib, have successfully targeted KRAS, many patients still experience a poor prognosis. Understanding the genomic differences present could improve treatment selection and identify new targets. In the Phase I/II KRYSTAL-I trial, Marcelo Negrao, M.D., and colleagues characterized the genomic features of 121 patients with KRAS G12C-mutant NSCLC treated with adagrasib. Overall, 32% of patients had longer survival with adagrasib monotherapy. High NRF2 signaling and/or the presence of KEAP1 and STK11 co-mutations were associated with shorter survival. The addition of an mTOR inhibitor improved treatment efficacy in lab models harboring KEAP1 and STK11 co-mutations, suggesting its therapeutic potential. The study highlights the importance of considering co-mutations and other genomic features in treatment selection to improve outcomes for patients with KRAS G12C-mutant NSCLC. Learn more in Clinical Cancer Research.
Combination therapy yields strong responses in patients with refractory lymphoma
Patients with refractory lymphomas, particularly those who did not benefit from chimeric antigen receptor (CAR) T cell therapy, do not respond well to subsequent treatments and face a poor prognosis. This highlights a need for more effective high-dose chemotherapy (HDC) combinations with autologous stem-cell transplantation. Preclinical studies showed marked synergy between the PARP inhibitor olaparib and HDC in refractory lymphoma in cell lines, leading Yago Nieto, M.D., Ph.D., and colleagues to evaluate the efficacy and safety of this combination in a Phase I trial. Among 50 adult patients, the overall and complete response rates were 100% and 90%, respectively. At a median follow-up of 30 months, the event-free survival (EFS) and overall survival (OS) rates were 72% and 82%, respectively. For 17 patients with prior CAR T cell therapy failure, the EFS and OS rates were 71% and 88%, respectively. These results suggest this combination is safe and promising for patients with refractory lymphomas. Learn more in Clinical Cancer Research.
Study finds novel biomarker, potential therapeutic target for renal medullary carcinoma
Renal medullary carcinoma (RMC) is a rare and aggressive kidney cancer involving the loss of the SMARCB1 tumor suppressor that mainly affects young individuals of African descent with the sickle cell trait. Patients with RMC have a poor prognosis and limited treatment options, and there is an unmet need for clinically relevant biomarkers for early detection. Researchers led by Pavlos Msaouel, M.D., Ph.D., used integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls to uncover potential biomarkers. They identified MUC16 – the gene encoding serum cancer antigen 125 (CA-125) – as one of the most significantly upregulated genes in RMC tumor tissues, correlating it to metastatic tumor burden. Further analysis of RMC cell lines revealed that SMARCB1 loss is necessary but not sufficient for MUC16 expression, explaining why elevated serum CA-125 levels are observed in most, but not all, RMC patients. The study suggests that serum CA-125 could serve as a clinical biomarker for RMC and highlights MUC16 as a potential therapeutic target. Learn more in Clinical Cancer Research.
Epigenetic pathway is involved in persistent inflammatory pain
Inflammation can sensitize neurons and lead to persistent pain. While studies have shown that this pain is associated with increases in expression of the TRPA1 and TRPV1 pain receptors, little is known about the underlying mechanisms driving this process. Researchers led by Hui-Lin Pan, M.D., Ph.D., and Krishna Ghosh, Ph.D., examined preclinical models of persistent inflammation to identify potential epigenetic pathways. They found the G9a enzyme is involved in modifying histones inside sensory neurons, which can control the accessibility of gene transcription regulatory elements. This increases access to and production of the TRPA1 and TRPV1 pain receptors, which then sensitize neurons and promote inflammatory pain. The study highlights the therapeutic potential of targeting G9a to reduce pain receptor activity and persistent inflammatory pain. Learn more in The Journal of Neuroscience.
Awards and Honors
- Amma Asare, M.D., Ph.D., was named a 2024 Hanna Gray Fellow by the Howard Hughes Medical Institute
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