JACK CHAN - Academia.edu (original) (raw)

Papers by JACK CHAN

Supplementary Figure 8. Proposed mechanisms and clinical application for the ACTIV+Pano treatment.

Supplementary Figure 3. Pano induced pancreatic tumor cell apoptosis.

Supplementary Figure 6. The infiltration of CD8+ cells to the Her2+ non-tumor regions.

Purpose:In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy... more Purpose:In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model.Experimental Design:We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano).Results:The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice.Conclusions:We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.

Journal of Curriculum Studies, 1996

Theory and Research in Social Education, 1993

Chinese clinical oncology, Apr 1, 2018

The immune system plays a complex role in the recognition/prevention, early eradication as well a... more The immune system plays a complex role in the recognition/prevention, early eradication as well as progression of cancer. Recently, we have witnessed great momentum in the field of immuno-oncology. Checkpoint inhibitors and chimeric antigen receptor T cell therapy have now entered the clinic, with impressive and durable clinical responses seen across a broad array of tumor types. There are several lines of evidence supporting the development of an immune targeted approach in breast cancer. Emerging data of early clinical trials evaluating monotherapy checkpoint inhibition have shown modest activity in breast cancer, in particular high grade and aggressive subtypes such as triple negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal B breast cancers. A considerable amount of effort is currently underway in exploring the use of combinatory strategies where therapies with distinct and potentially complementary mechanisms of actions may further enhance the immune response broadening out the group of breast cancer patients who would benefit from this strategy of cancer treatment. In this review, we discuss approaches to targeting the immune system in breast cancer adopted through understanding why the host immune system has failed in natural tumor suppression as well as the processes evolved by the tumor to circumvent an active immune system.

Cancer Research, Apr 14, 2023

Cancer Cell, Jun 1, 2020

In this issue of Cancer Cell, Gurusamy et al. use a CRISPR-Cas9 screening approach to demonstrate... more In this issue of Cancer Cell, Gurusamy et al. use a CRISPR-Cas9 screening approach to demonstrate that deletion of p38 increases multiple phenotypic qualities of effective anti-tumor T cells. Preconditioning T cells with a p38 inhibitor enhances anti-tumor efficacy of adoptive immunotherapy.

JCO oncology practice, Mar 1, 2021

QUESTION ASKED: Can a comprehensive cancer center be organized to make operations pandemic proof ... more QUESTION ASKED: Can a comprehensive cancer center be organized to make operations pandemic proof and achieve continuity of cancer care during the COVID-19 pandemic? SUMMARY ANSWER: Through the coordinated efforts of a Disease Outbreak Response (DORS) Taskforce, it is possible to avoid nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmissions among patients and staff without compromising on care delivery at a comprehensive cancer center. WHAT WE DID: The DORS Taskforce rapidly implemented a holistic pandemic response plan for the National Cancer Centre Singapore (NCCS) and its satellite clinics with measures for strict infection prevention, manpower preservation, prudent resource allocation, and adaptations to standard-of-care treatments. The number and results of polymerase chain reaction swab tests among patients and staff who met the defined criteria for testing of SARS-CoV-2 infection were tracked. Output indicators at the main center from February 3 to May 23, 2020, including outpatient attendances, chemotherapy treatments, radiation therapy treatments, cancer-related surgeries, imaging studies, and biopsies performed, were also analyzed in aggregate and on a monthly and weekly basis. They were compared with the corresponding period in 2019 to assess the impact of the pandemic on continuity of cancer care.

Proceedings of the National Academy of Sciences of the United States of America, Nov 25, 2019

SignificanceRegressions of some blood cancer can follow infusion of patients’ own T cells gene-mo... more SignificanceRegressions of some blood cancer can follow infusion of patients’ own T cells gene-modified to express a chimeric antigen receptor (CAR). These regressions are associated with extensive proliferation and engraftment of CAR T cells. However, for most common solid cancers, CAR T cells encounter antigen in a microenvironment that is immunosuppressive and lacking T cell support, and significant engraftment does not always occur. Here, we deliver enterotoxins or bispecific antibody to provide CAR T cells with support signals from antigen-presenting cells in lymphoid tissue, away from the tumor microenvironment. We demonstrate that this enables CAR T cell activation and proliferation, leading to enhanced responses against solid tumors in mice. This approach could lead to effective treatments for many common cancers.

Supplementary Figure 4. Pano did not enhance the cytotoxicity of CARaMEL cells nor oncolysis of V... more Supplementary Figure 4. Pano did not enhance the cytotoxicity of CARaMEL cells nor oncolysis of VV-gp100.

Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR... more Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR T cell-mediated cytotoxicity.

Elements, Jan 26, 2021

Objective: To evaluate the cost-effectiveness of olaparib as a maintenance treatment versus routi... more Objective: To evaluate the cost-effectiveness of olaparib as a maintenance treatment versus routine surveillance (RS) in patients with BRCA mutated (BRCAm) advanced ovarian cancer (OC) following response to first-line platinum-based chemotherapy in Singapore. Methods: A 4-health state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of olaparib versus RS from a healthcare payer perspective. Progression-free survival, time to second disease progression, and overall survival were estimated using SOLO-1 data and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be no longer at risk of progression. Mortality rates were based on all-cause mortality, adjusted based on BRCA1/2 mutation. Health state utilities and adverse event frequencies were from SOLO-1. Drug costs were from local public healthcare institutions. Healthcare resource usage and costs were from local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results. Results: The base-case analysis of olaparib maintenance therapy versus RS resulted in an ICER of Singapore dollar (SGD) 19,822 per quality-adjusted life-year (QALY) gained. The ICER was most sensitive to variations in the discount rate. PSA demonstrated that olaparib had an 87% probability of being cost-effective versus RS at a willingness-to-pay of SGD 60,000 per QALY gained. Conclusion: Olaparib has a high potential of being a cost-effective maintenance treatment versus RS for patients with BRCA1/2m advanced OC after response to first-line chemotherapy in Singapore.

Clinical Cancer Research, Sep 2, 2021

Therapeutic Advances in Medical Oncology, 2019

Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-nega... more Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC.

Nature Immunology, May 18, 2020

Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor... more Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.

Journal of Curriculum Studies, Sep 1, 1995

Frontiers in Oncology, Feb 12, 2019

Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the ... more Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced ex vivo and expanded in vitro for infusion into patients. Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.