Artificial intelligence（AI) such as Watson for Oncology (WfO) is developed to assist in tumor therapy by providing evidence-based treatment options or recommendations with priority and personality. There have been some reports that recommendations provided by WfO and oncologists are highly consistent while some specialists doubt the accuracy of WfO recommendations. As China has its unique medical situations such as tense doctor-patient relationship, high physician's work pressure, low MDT launch rate, new drug availability and different guidelines from USA, etc. further exploration of the clinical application of WfO and establishment of a quality control system is needed in China.
In the past few years, immunotherapy has become an integral part of cancer treatment. In particular, immune checkpoint inhibitors (ICIs) blocking PD-1, PL-L1 or CTLA4 have been approved in multiple cancer types. However, except in melanoma where the response rate is over 50%, most cancer types exhibit an ICI response rate between 10 to 20% to ICIs, suggesting the need for a predictive biomarker. In addition, while some patients experienced long-lasting response towards ICI treatment, most patients develop resistance. For ICI reflected patients, additional biomarkers are also needed to evaluate strategy for subsequent treatment. Finally, some studies also show that certain patients experienced disease hyper-progression when treated with ICIs, further demonstrate the need for a biomarker to exclude individuals who may suffer from unnecessary adverse effects from ICIs. The expression level of PD-L1 has already been used to predict treatment response for ICIs. Tumor mutation burden (TMB) is a promising biomarker currently under intense investigation. Alteration in several pathways and genes have also been shown to confer sensitivity or resistance to ICIs. In addition to tumor cells, the composition and functional status of immune cells in the tumor microenvironment have also played an important role in determining the response to ICIs. A comprehensive strategy incorporating tumor mutation and tumor microenvironment will be presented to predict the benefit of immunotherapy in clinics.
CRISPR-Cas9-based technologies have revolutionized experimental manipulation of the human genome. I will highlight some recent advances in the applications of CRISPR-Cas9 technologies to cancer and related diseases. In addition, I will summarize recent work from my lab in this space focused on dissecting functional domains in genes, identifying cancer-specific vulnerabilities, and defining quiescent-like states in human brain tumors.
Advances in targeted therapy and immunotherapy have transformed the landscape of metastatic non-small cell lung cancer (NSCLC) over the last decade. With the identification of distinct NSCLC molecular subtypes on cancer profiling, treatments have evolved to ever more precisely target the specific molecular drivers of cancer. The use of checkpoint inhibitors has also enabled patients to overcome cancer more effectively. However, there are still a meaningful proportion of patients who do not benefit from such treatments. We describe here a refined approach to more effectively identify NSCLC patients who will benefit from appropriate treatments. Both multiplexed PD-L1 immunofluorescence and ultradeep amplicon-based sequencing in tissue and blood are discussed.
Anaplastic lymphoma kinase (ALK) gene rearrangement occurs in around 3-5% of patients with non-small cell lung cancer. Crizotinib is the first oral target therapy that approved for use in this group in 2011 based on its superiority in response rate and prolonging survival over chemotherapy. However, progression inevitably occurs after a median of around 10 months and intra-cranial failure is another commonly encountered situation. Luckily in subsequent years, newer generation target therapies emerged (including Ceritinib and Alectinib) and demonstrated efficacy in patients who failed or intolerant to Crizotinib. Brigatinib is another second generation ALK inhibitor which had recently been approved for use in this situation as well. This talk will provide a review on the current data available including the efficacy and safety profile.
The incorporation of immune checkpoint blockade into the treatment of many common cancers has revolutionized solid tumor oncology and solidified immunotherapy as the fourth pillar of oncology therapeutics. Breast cancer patients and advocates, as well as the breast oncology scientific community, celebrate the first US Food and Drug Administration–approved immune checkpoint inhibitor, atezolizumab, combined with nab-paclitaxel for the treatment of advanced triple-negative breast cancer—the most challenging breast cancer subtype. Beyond immune checkpoint blockade, a number of other exciting immuno-oncology modalities are under evaluation for breast cancer that focus on enhancing immune response against tumor-associated antigens. These include vaccines, antibody-drug conjugates, oncolytic viruses, and, perhaps most directly, adoptive cellular immunotherapy using genetically modified T cells to directly interact with tumor antigens. T-cell receptors recognize tumor antigens in the context of major histocompatibility complex and chimeric antigen receptor (CAR) T cells, which combine the specificity of an antibody with the cytotoxic function of T cells. Our group is evaluating CAR T cells in two breast cancer patient populations including ROR1-positive advanced triple-negative breast cancer and advanced breast cancer expressing a cleaved form of MUC1 (ClinicalTrials.gov identifiers: NCT02706392 and NCT04020575).
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different tumors, including ovarian cancer. A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. During this talk, I will cover emerging clinical data from multiple trials which have evaluated PARP inhibitors in ovarian cancer irrespective of BRCA mutation status.
Stereotactic radiosurgery for large brain metastases- Preop, Postop or no op?
Stereotactic radiosurgery (SRS)/ stereotactic radiotherapy (SRT) has become one of the standard treatment options for patients with limited brain metastases. Controversies exist regarding the best strategy to incorporate both surgery and SRS/ SRT in patients with large brain metastases. SRS/ SRT alone, after surgical resection or before surgical resection have been used to manage patients with large brain metastases. This lecture will cover the pros and cons and the outcomes with each strategy.
Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. In this presentation, we will discuss the physics of proton beam therapy for lung cancer, present the existing data in locally advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning
Electrical therapy is an emerging non invasive technology for the treatment of solid tumors. Tumor treating fields (TTF) are alternating electrical fields in a specific frequency (100-300kHz) designed to inhibit tumor cell division though preventing normal polymerization of mitotic spindles as well as cleavage site of the dividing cell. This mechanism of cell death has been demonstrated in multiple cell lines as well as animal models of solid tumors. Clinically, tumor treating fields are delivered through a portable medical device with a treatment plan designed based on tumor location. The first confirmed clinical benefit was in recurrent glioblastoma where TTF were equivalent to physicians best choice chemotherapy. Subsequently tumor treating fields were found to have a dose dependent increase in median overall survival for new diagnosis glioblastoma when added to radiation and temozolomide chemotherapy. This has lead to a new standard of care for adult glioblastoma. Most recently a multicenter phase II study of unresectable malignant pleural mesothelioma found increased median overall survival compared to historical controls with addition of tumor treating fields to standard chemotherapy. There are ongoing clinical trials for many solid malignancies including pancreatic adenocarcinoma, hepatocellular carcinoma, meningioma and lung cancer. Electrical therapy has transformed the treatment of glioblastoma and will likely become and new modality for other advanced solid tumors.
Tony Wong, PhD
The talk will present two new developments in proton beam therapy in quality improvement with machine learning and FLASH radiotherapy.
Discrepancies between planned and delivered spot positions and dose (MU) in proton pencil beam scanning (PBS) deliveries can introduce error in dose distributions for patient treatments. These discrepancies can be effectively quantified using PBS irradiation log files which contain information about the delivered spot positions and MU. In this work, a data set of delivered spots was generated from PBS log files. This data set was used to train several machine learning models to predict PBS spot deliveries for patient treatments. Analysis across multiple patients and disease sites indicate that the predicted spot delivery positions and MU were in closer agreement to the delivered parameters than the planned parameters. Incorporating this predictive model in treatment planning can allow us to generate a more realistic dose distribution, which accounts for potential delivery uncertainties introduced during patient PBS treatments.
FLASH radiotherapy is an experimental technique delivering radiation at ultra-high dose rates of at least 40 Gy/s. FLASH RT appears to spare normal tissue while preserving full target control probability. Most cyclotron-based proton treatment units are capable of delivering this promising treatment. The talk will also give an update on the potential use of protons for FLASH RT.
Precision Radiotherapy for Liver Cancers
With the recent technologic advancements in precision radiotherapy, Stereotactic Body Radiation Therapy (SBRT) has become an efficacious and safe treatment option for both primary and secondary liver cancers.
SBRT treatment for liver cancer patients at the BC Cancer Agency, Vancouver Center started in 2010 using a motion encompassing Internal Target Volume (ITV) technique. Dynamic Tracking (DT) was commissioned for clinical treatment of liver cancer patients in October 2017.
Comparative planning studies between DT and ITV techniques for 22 primary liver cancer patients showed a significant decrease in the size of the Planning Target Volume and the mean liver dose, both favoring DT. Three months post irradiation toxicity data for the same cohort treated with DT showed only a 4% rate of liver toxicity. This compares very favorably with our historical cohort that was treated with the ITV technique.
Conclusion: DT is safe with a very low risk of clinically important acute toxicity.
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