Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.

Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.

Case report: Fatal overwhelming post-splenectomy infection in a patient with metastatic angiosarcoma treated with immunotherapy.

A patient in his 40s with splenic angiosarcoma metastatic to the liver underwent splenectomy, chemotherapy, and partial hepatectomy before being treated on a clinical trial with CTLA4 and PD1 inhibitors. He had received pneumococcal and meningococcal vaccines post-splenectomy. On week 10, he developed grade 3 immune-related colitis, successfully treated with the anti-tumor necrosis factor-alpha inhibitor infliximab and steroids. After 4 cycles of treatment, scans showed partial response. He resumed anti-PD1 therapy, and 6 hours after the second dose of anti-PD1 he presented to the emergency room with hematemesis, hematochezia, hypotension, fever, and oxygen desaturation. Laboratory tests demonstrated acute renal failure and septicemia (Streptococcus pneumoniae). He died 12 hours after the anti-PD1 infusion from overwhelming post-splenectomy infection (OPSI). Autopsy demonstrated non-viable liver tumors among other findings. In conclusion, patients undergoing immunotherapy and with prior history of asplenia should be monitored closely for OPSI as they may be at increased risk.

Autologous engineered T cell receptor therapy in advanced cancer.

To overcome challenges associated with adoptive cell therapy (ACT), we developed a personalized autologous T-cell therapy program. Patients with advanced cancer with HLA-A *02:01 allele and tumor expression of PRAME, MAGEA1, MAGEA4, MAGEA8, NY-ESO-1, COL6A3 exon 6, MXRA5, and/or MMP1 underwent leukapheresis and T-cell product manufacturing. Patients received lymphodepletion, IMA101 infusion and interleukin 2 for 14 days. Of 214 screened patients, 14 were treated (6, IMA101; 8, IMA101 and atezolizumab). The most common adverse events were cytokine release syndrome (G1, n = 6; G2, n = 4) and cytopenia. At 6 weeks, 12 (85.7%) patients had stable disease. Three patients had prolonged disease stabilization for 12.9, 7.3, and 13.7 months, respectively. The median progression-free survival and overall survival were 3.4 months and 9.4 months, respectively. Target-specific T cells expanded to constitute up to 78.7% of CD8+ cells. In conclusion, IMA101 was feasible and well tolerated, leveraging the potential of multi-targeted ACT that warrants further investigation.

Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy.

T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies.

Molecular tumour boards - current and future considerations for precision oncology.

Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology.

Precision Oncology: Evolving Clinical Trials across Tumor Types.

Advances in molecular technologies and targeted therapeutics have accelerated the implementation of precision oncology, resulting in improved clinical outcomes in selected patients. The use of next-generation sequencing and assessments of immune and other biomarkers helps optimize patient treatment selection. In this review, selected precision oncology trials including the IMPACT, SHIVA, IMPACT2, NCI-MPACT, TAPUR, DRUP, and NCI-MATCH studies are summarized, and their challenges and opportunities are discussed. Brief summaries of the new ComboMATCH, MyeloMATCH, and iMATCH studies, which follow the example of NCI-MATCH, are also included. Despite the progress made, precision oncology is inaccessible to many patients with cancer. Some patients' tumors may not respond to these treatments, owing to the complexity of carcinogenesis, the use of ineffective therapies, or unknown mechanisms of tumor resistance to treatment. The implementation of artificial intelligence, machine learning, and bioinformatic analyses of complex multi-omic data may improve the accuracy of tumor characterization, and if used strategically with caution, may accelerate the implementation of precision medicine. Clinical trials in precision oncology continue to evolve, improving outcomes and expediting the identification of curative strategies for patients with cancer. Despite the existing challenges, significant progress has been made in the past twenty years, demonstrating the benefit of precision oncology in many patients with advanced cancer.