Recent developments include a new treatment option for relapsed/refractory mantle cell lymphoma, a better understanding of protein variants that trigger tumor cell death and activate antitumor immunity, insights into the relationship between sickle cell trait and renal medullary carcinoma, clearer awareness of the clinical relevance of CD8 T cell state in acute myeloid leukemia, and an understanding of the distinct neuronal pathways triggered by chemotherapy and nerve injury.
Phase I/II trial shows safety and efficacy of pirtobrutinib in advanced MCL
Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) – an aggressive subtype of B-cell non-Hodgkin lymphoma – initially respond well to covalent Bruton tyrosine kinase inhibitors (cBTKis) but eventually develop resistance, underscoring the need for more effective therapeutic strategies. Pirtobrutinib – a highly selective non-covalent BTKi – inhibits both normal and mutant BTK, providing a potential alternative. In a first-in-human Phase I/II clinical trial, researchers led by Michael Wang, M.D., examined the safety and efficacy of pirtobrutinib monotherapy in 90 patients with R/R MCL who previously received cBTKi treatment. The objective response rate was 57.8%, including 20% with complete responses, and the 12-month estimated duration of response rate was 57.1%. The most common side effects were fatigue, diarrhea and dyspnea. Grade 3 adverse events were infrequent and only 3% of patients discontinued treatment. The study demonstrated that pirtobrutinib was safe and showed durable efficacy in R/R MCL. Based on this data, the Food and Drug Administration granted accelerated approval for pirtobrutinib in R/R MCL in Jan. 2023. Learn more in the Journal of Clinical Oncology.
Specific protein variants trigger cancer cell death and improve antitumor response
The gasdermin B (GSDMB) protein can trigger cancer-associated pyroptosis – a form of programmed cell death that activates antitumor immune responses – but its exact role is controversial. The protein has multiple variants created from mRNA splicing, and these can have either anti- or pro-tumor functions. In this study, researchers led by Qing Kong, Ph.D., and Zhibin Zhang, Ph.D., examined six GSDMB splicing variants to provide insights into which are involved in pyroptosis. Relative to other variants, isoforms 3/4 were cytotoxic for tumor cells, triggering pyroptosis and resulting in better antitumor outcomes in bladder and cervical cancer models. The study suggests that tumors may be preferentially generating non-cytotoxic GSDMB variants in order to protect against pyroptosis. It also highlights the potential for therapeutic strategies that can increase production of cytotoxic GSDMB variants to improve antitumor immunity and enhance immunotherapy response. Learn more in Science Immunology.
Link between sickle cell trait and SMARCB1 loss observed in renal medullary carcinoma
Renal medullary carcinoma (RMC) is a rare and aggressive form of kidney cancer that typically develops in young adults with sickle cell trait (SCT). Loss of the SMARCB1 tumor suppressor is a defining characteristic of RMC tumors. To better understand the mechanisms driving RMC and to improve treatment options, researchers led by Giannicola Genovese, M.D., Ph.D., Pavlos Msaouel M.D., Ph.D., and Melinda Soeung, Ph.D., investigated whether the loss of SMARCB1 provides a survival advantage in the presence of SCT. They demonstrated that a lack of oxygen induced by SCT leads to SMARCB1 degradation, protecting cells from hypoxic stress. The results suggest that SMARCB1 loss improves the survival of RMC cells under hypoxia, potentially explaining why SMARCB1-deficient tumors are resistant to therapeutic agents targeting hypoxia pathways. These insights may help researchers develop more effective treatments against RMC. Learn more in Proceedings of the National Academy of Sciences.
CD8 T Cells in AML display continuous differentiation and clonal hyperexpansion
Limited research is available on CD8 T cell exhaustion in hematologic cancers, specifically acute myeloid leukemia (AML). In a study led by Hussein Abbas, M.D, Ph.D., researchers characterized CD8 T cells from healthy donors as well as newly diagnosed (NewlyDx) and relapsed/refractory (R/R) AML patients. They discovered very few “exhausted” cells, with effector CD8 T cells from NewlyDx and R/R patients having different cytokine and metabolic profiles than the classic exhaustion signature seen in solid tumors. Researchers refined a 25-gene signature associated with poor outcomes in previously untreated AML patients, suggesting that the CD8 cell state may be clinically relevant. Analysis of T cell receptor sequencing data also revealed an increase in clonal hyperexpansion in R/R patient cells. The study highlights shared characteristics between CD8 cells in AML and those in solid cancer, suggesting that immune-based therapy in AML is likely to be most successful in earlier stages when CD8 T cells can afford plasticity. Learn more in Cancer Immunology Research.
Chemotherapy and nerve injury induces chronic pain via different sensory neurons
Treatment with chemotherapy is necessary for many patients with cancer, but it can sometimes cause chronic pain similar to traumatic nerve injuries. Studies have shown chemotherapy-induced neuropathy augments glutamate NMDA receptor (NMDAR) activity in the spinal cord, but little is known about the pathways involved. Researchers led by Yuying Huang, Ph.D., Shao Rui-Chen, M.D., and Hui-Lin Pan, M.D., Ph.D., found that chemotherapy triggers NMDAR activity in specific excitatory neurons. Removing NMDAR from these primary sensory neurons diminished chemotherapy-induced pain in laboratory models. Alternatively, chronic pain from traumatic nerve injury mainly resulted from the NMDAR expressed in different spinal neurons. The results suggest that chronic pain following nerve injury and chemotherapy is triggered by the NMDAR in different neurons and pathways, highlighting potential cellular targets to help treat these separate conditions. Learn more in The Journal of Neuroscience.
In case you missed it
Read below to catch up on recent MD Anderson press releases.
- MD Anderson awarded over $5.7 million from Break Through Cancer to support AML research
- Combined delivery of engineered virus with immunotherapy is safe and improves outcomes in subset of patients with glioblastoma
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