Journal Articles

The AIM2 and NLRP3 inflammasomes trigger IL-1–mediated antitumor effects during radiation

Han et al. observed that, relative to WT, casp1 knockout mice were resistant to tumor irradiation therapy. They examined individual components of this CASP1-dependent (IL-1-dependent) response to tumor irradiation by utilizing an array of gene- and cell type-specific knockout and Cre recombinase transgenic mice. Extracellular vesicular components of irradiated tumors activated the AIM2 inflammasome, and tumor supernatant induced IL-1 production through NLRP3. These two pathways coordinated in the production of IL-1, resulting in DC activation and cross-priming of intratumoral CD8+ T cells.

Contributed by Margot O’Toole

Han et al. observed that, relative to WT, casp1 knockout mice were resistant to tumor irradiation therapy. They examined individual components of this CASP1-dependent (IL-1-dependent) response to tumor irradiation by utilizing an array of gene- and cell type-specific knockout and Cre recombinase transgenic mice. Extracellular vesicular components of irradiated tumors activated the AIM2 inflammasome, and tumor supernatant induced IL-1 production through NLRP3. These two pathways coordinated in the production of IL-1, resulting in DC activation and cross-priming of intratumoral CD8+ T cells.

Contributed by Margot O’Toole

ABSTRACT: The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in Casp1-/- mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either Aim2-/- or Nlrp3-/- mice remained sensitive to radiation, like WT mice, whereas Aim2-/-Nlrp3-/- mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in Casp1-/- and Aim2-/-Nlrp3-/- mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.

Author Info: (1) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. (2) Institute of Biophysics, Chinese Academy of Sciences. Beijing, China. (3) Department of Radiation

Author Info: (1) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. (2) Institute of Biophysics, Chinese Academy of Sciences. Beijing, China. (3) Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA. (4) Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. hasan.zaki@utsouthwestern.edu yang-xin.fu@utsouthwestern.edu.

Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches. METHODS: To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) by testing the combination with a gene-therapy approach using a bispecific T-cell engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EphA2 adenovirus (EAd)). The combinatorial approach was tested in vitro, in vivo and thoroughly characterized at a molecular level. RESULTS: After confirming the relevance of EphA2 as target in pHGGs, documenting a significant correlation with worse clinical outcome of the patients, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, on coculture with T cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profiles and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. The gene-expression analysis of tumor cells and T cells, after coculture, revealed the importance of both EphA2-BiTE and costimulation in the proposed system. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model. CONCLUSIONS: The combination of OA and EphA2-BiTE gene therapy strongly enhances the antitumor activity of OA, inducing the eradication of highly resistant tumor cells, thus supporting the clinical translation of the approach.

Author Info: (1) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (2) Department of Paediatric Haematology and Onc

Author Info: (1) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (2) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (3) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (4) Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (5) Pathology Unit, Department of Laboratories, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (6) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (7) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (8) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (9) The FIRC Institute of Molecular Oncology, IFOM, Milano, Italy. Institute of Molecular Genetics National Research Council, Pavia, Italy. (10) The FIRC Institute of Molecular Oncology, IFOM, Milano, Italy. (11) Flow Cytometry and Histology Core Facilities, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (12) Flow Cytometry and Histology Core Facilities, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (13) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (14) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (15) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (16) Baylor College of Medicine Center for Cell and Gene Therapy, Houston, Texas, USA. (17) Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA. (18) Baylor College of Medicine Center for Cell and Gene Therapy, Houston, Texas, USA. (19) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. Department of Pediatrics, Sapienza University of Rome, Roma, Italy. (20) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy. (21) Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, Rome, Italy francesca.delbufalo@opbg.net.

Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes co-expressing CD39, CD103, and PD-1 in ovarian cancer

PURPOSE: Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches. EXPERIMENTAL DESIGN: Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens. RESULTS: Co-expression of CD39, CD103, and PD-1 ("triple-positive" phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Tregs) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced TCR diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts. CONCLUSIONS: Co-expression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39 and TIGIT.

Author Info: (1) Deeley Research Center, BC Cancer. (2) Deeley Research Centre, BC Cancer. (3) Deeley Research Centre, BC Cancer. (4) Deeley Research Center, BC Cancer. (5) Centre for Lymphoid

Author Info: (1) Deeley Research Center, BC Cancer. (2) Deeley Research Centre, BC Cancer. (3) Deeley Research Centre, BC Cancer. (4) Deeley Research Center, BC Cancer. (5) Centre for Lymphoid Cancer, BC Cancer Agency. (6) Lymphoid Cancer Research, BC Cancer Agency. (7) Deeley Research Center, BC Cancer. (8) Deeley Research Centre, British Columbia Cancer Agency. (9) Deeley Research Centre, British Columbia Cancer Agency. (10) BC Cancer Agency. (11) Deeley Research Centre, BC Cancer bnelson@bccrc.ca.

HHLA2 predicts better survival and exhibits inhibited proliferation in epithelial ovarian cancer

PURPOSE: The role of HHLA2, a new immune checkpoint ligand, is gradually being elucidated in various solid tumours. However, its role in ovarian cancer remains unclear; thus, its expression profile and clinical significance in ovarian cancer must be examined. METHODS: We performed immunohistochemistry to examine HHLA2 expression in 64 ovarian cancer tissues and 16 normal ovarian tissues. The relationships between HHLA2 expression and clinicopathological features, prognosis, and CD8(+) tumour-infiltrating lymphocytes (TILs) in patients were analysed. Additionally, the Cancer Cell Line Encyclopedia database was used to analyse the correlation between HHLA2 expression and PD-L1 or B7x expression. Furthermore, the biological function of HHLA2 in ovarian cancer cells was initially explored. RESULTS: Only 17.2% of ovarian cancer patients showed HHLA2 expression, which was significantly associated with the differentiation of ovarian cancer cells (p_=_0.027), and well-differentiated tumours expressed higher levels of HHLA2. The density of CD8(+) TIL was associated with increased HHLA2 expression (p_=_0.017), and the CD8(+) TIL count was higher in the HHLA2-positive group than that in the HHLA2-negative group (p_=_0.023). Moreover, multivariate analysis identified HHLA2 expression as an independent prognostic factor that predicted improved survival (p_=_0.049; HR_=_0.156; 95% CI_=_0.025-0.992). Additionally, we also found that overexpressing HHLA2 inhibited the proliferation of ovarian cancer cells. CONCLUSION: HHLA2 is associated with tumour differentiation and high CD8(+) TIL levels; and predicts improved survival in ovarian cancer. Along with previously reported findings that HHLA2 behaves as a co-stimulatory ligand, our study suggests that the loss of HHLA2 may contribute to the immunosuppressive microenvironment and progression of ovarian cancer.

Author Info: (1) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (2) Department of

Author Info: (1) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (2) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (3) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (4) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (5) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (6) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. (7) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. pengyp@mail.sysu.edu.cn. (8) Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yingfeng Road No.33, Haizhu District, Guangzhou, Guangdong, China. zhbzhong@mail.sysu.edu.cn.

The Association Between Glucocorticoid Administration and the Risk of Impaired Efficacy of Axicabtagene Ciloleucel Treatment: A Systematic Review

BACKGROUND: Glucocorticoid is one of the common and important strategies for the treatment of chimeric antigen receptor T (CAR-T) cell therapy-related toxicity. However, there has been a theoretical concern about whether glucocorticoids use can impact the expansion of CAR-T cells and thus impair its efficacy. Hence, we reviewed studies related to the Axicabtagene ciloleucel (Axi-cel), a first-class and widely used CAR-T cell product, to elucidate the association between glucocorticoids administration and efficacy of Axi-cel. METHOD: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library to identify studies of Axi-cel that used glucocorticoids as an intervention for the treatment of CAR-T cell-related adverse events and respectively evaluated any efficacy endpoints of intervention and controlled cohorts, published up to February 17, 2020. There were no restrictions on research type and language. RESULTS: A total of eight studies with 706 patients were identified in the systematic review. Except for one study found that high cumulative dose, prolonged duration and early use of glucocorticoids could shorten progression-free survival and/or overall survival, and another study that found a negative effect of glucocorticoids administration on overall survival in univariate analysis but disappeared in multivariate analysis, none of other studies observed a statistically significant association between glucocorticoids administration and progression-free survival, overall survival, complete response, and overall response rate. CONCLUSION: Our study indicated that the association between glucocorticoids therapy and the efficacy of CAR-T cell may be affected by cumulative dose, duration, and timing. There is currently no robust evidence that glucocorticoids can damage the efficacy of CAR-T cell, but the early use of glucocorticoids should be cautiously recommended.

Author Info: (1) Hengyang Medical College, University of South China, Hengyang, China. (2) Department of Neurosurgery, The First Affiliated Hospital, University of South China, Hengyang, China.

Author Info: (1) Hengyang Medical College, University of South China, Hengyang, China. (2) Department of Neurosurgery, The First Affiliated Hospital, University of South China, Hengyang, China. (3) Hengyang Medical College, University of South China, Hengyang, China. (4) Department of Neurosurgery, The First Affiliated Hospital, University of South China, Hengyang, China. (5) Department of Neurosurgery, The First Affiliated Hospital, University of South China, Hengyang, China.

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma

BACKGROUND: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone. METHODS: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40_Gy in 5 fractions or 24_Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3_months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment. RESULTS: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated. CONCLUSION: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

Author Info: (1) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. (2) Providence Cancer Institute, Portland, Oregon, USA. Earle A Ch

Author Info: (1) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. (2) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. Division of Radiation Oncology, The Oregon Clinic, Portland, Oregon, USA. (3) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. Division of Radiation Oncology, The Oregon Clinic, Portland, Oregon, USA. (4) Department of Pathology, Providence Health and Services- Oregon, Portland, Oregon, USA. (5) Department of Pathology, Providence Health and Services- Oregon, Portland, Oregon, USA. (6) Providence Cancer Institute, Portland, Oregon, USA. (7) Providence Cancer Institute, Portland, Oregon, USA. Head and Neck Institute, Portland, Oregon, USA. (8) Head and Neck Institute, Portland, Oregon, USA. (9) Providence Cancer Institute, Portland, Oregon, USA. (10) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. Department of Pathology, Providence Health and Services- Oregon, Portland, Oregon, USA. (11) Earle A Chiles Research Institute, Portland, Oregon, USA. (12) Earle A Chiles Research Institute, Portland, Oregon, USA. (13) Providence Cancer Institute, Portland, Oregon, USA. (14) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. (15) Providence Cancer Institute, Portland, Oregon, USA. Earle A Chiles Research Institute, Portland, Oregon, USA. (16) Providence Cancer Institute, Portland, Oregon, USA richard.bell@providence.org. Earle A Chiles Research Institute, Portland, Oregon, USA.

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

BACKGROUND: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. METHOD: We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15. RESULTS: Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers. CONCLUSIONS: ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Author Info: (1) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Division of Oncology, University of Washington, Seattle, WA, USA. Department of Surgery, U

Author Info: (1) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Division of Oncology, University of Washington, Seattle, WA, USA. Department of Surgery, University of Washington, Seattle, WA, USA. (2) Poseida Therapeutics, San Diego, CA, USA. (3) Division of Pediatric Hematology/Oncology, University of California, Los Angeles, California, USA. (4) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. (5) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. (6) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Division of Oncology, University of Washington, Seattle, WA, USA. Department of Internal Medicine, Virginia Mason Medical Center, Seattle, WA, USA. (7) MD Anderson, Houston, TX, USA. (8) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. (9) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. (10) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. (11) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Division of Oncology, University of Washington, Seattle, WA, USA. (12) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Division of Oncology, University of Washington, Seattle, WA, USA. (13) Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, WA, USA. (14) Department of Surgery, University of Washington, Seattle, WA, USA. (15) Division Hematology and Oncology, University of California, Los Angeles, UK. (16) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Sensei Biotherapeutics, Gaithersburg, Boston, MD, USA. (17) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Sensei Biotherapeutics, Gaithersburg, Boston, MD, USA. (18) Department of Radiation Oncology, University of Washington, Seattle, WA, USA. (19) Sarcoma, Royal Marsden Hospital and Institute of Cancer Research, London, UK. (20) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA. Department of Surgery, University of Washington, Seattle, WA, USA. Lyell Immunopharma, Seattle, WA, USA. (21) MD Anderson, Houston, TX, USA. (22) Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA Seth.pollack@northwestern.edu. Department of Surgery, University of Washington, Seattle, WA, USA. Division of Oncology, Northwestern University, Chicago, IL, USA.

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.

Author Info: (1) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Schulich School of Medicine, Western University, London, ON, Canada. (2) Cancer Therape

Author Info: (1) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Schulich School of Medicine, Western University, London, ON, Canada. (2) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (3) Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada. (4) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (5) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (6) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada. (7) Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. (8) Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. (9) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada. (10) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada. (11) Learning Services, The Ottawa Hospital, Ottawa, ON, Canada. (12) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada. (13) Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada. (14) Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada. Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (15) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada. (16) Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. Faculty of Medicine, University of Ottawa, Ottawa, Canada. Department of Medicine and The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Development and validation of MRI-based deep learning models for prediction of microsatellite instability in rectal cancer

BACKGROUND: Microsatellite instability (MSI) predetermines responses to adjuvant 5-fluorouracil and immunotherapy in rectal cancer and serves as a prognostic biomarker for clinical outcomes. Our objective was to develop and validate a deep learning model that could preoperatively predict the MSI status of rectal cancer based on magnetic resonance images. METHODS: This single-center retrospective study included 491 rectal cancer patients with pathologically proven microsatellite status. Patients were randomly divided into the training/validation cohort (n = 395) and the testing cohort (n = 96). A clinical model using logistic regression was constructed to discriminate MSI status using only clinical factors. Based on a modified MobileNetV2 architecture, deep learning models were tested for the predictive ability of MSI status from magnetic resonance images, with or without integrating clinical factors. RESULTS: The clinical model correctly classified 37.5% of MSI status in the testing cohort, with an AUC value of 0.573 (95% confidence interval [CI], 0.468 ~ 0.674). The pure imaging-based model and the combined model correctly classified 75.0% and 85.4% of MSI status in the testing cohort, with AUC values of 0.820 (95% CI, 0.718 ~ 0.884) and 0.868 (95% CI, 0.784 ~ 0.929), respectively. Both deep learning models performed better than the clinical model (p < 0.05). There was no statistically significant difference between the deep learning models with or without integrating clinical factors. CONCLUSIONS: Deep learning based on high-resolution T2-weighted magnetic resonance images showed a good predictive performance for MSI status in rectal cancer patients. The proposed model may help to identify patients who would benefit from chemotherapy or immunotherapy and determine individualized therapeutic strategies for these patients.

Author Info: (1) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China. Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forc

Author Info: (1) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China. Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, China. (2) Institute of Advanced Research, InferVision, Beijing, China. (3) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China. (4) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China. Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, China. (5) Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, China. (6) Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. (7) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China. (8) Institute of Advanced Research, InferVision, Beijing, China. (9) Institute of Advanced Research, InferVision, Beijing, China. (10) Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.

Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma

OBJECTIVE: The gut microbiome plays an important role in systemic inflammation and immune response. Microbes can translocate and reside in tumour niches. However, it is unclear how the intratumour microbiome affects immunity in human cancer. The purpose of this study was to investigate the association between intratumour bacteria, infiltrating CD8+ T cells and patient survival in cutaneous melanoma. METHODS: Using The Cancer Genome Altas's cutaneous melanoma RNA sequencing data, levels of intratumour bacteria and infiltrating CD8+ T cells were determined. Correlation between intratumour bacteria and infiltrating CD8+ T cells or chemokine gene expression and survival analysis of infiltrating CD8+ T cells and Lachnoclostridium in cutaneous melanoma were performed. RESULTS: Patients with low levels of CD8+ T cells have significantly shorter survival than those with high levels. The adjusted hazard ratio was 1.57 (low vs high) (95% confidence interval: 1.17-2.10, p = 0.002). Intratumour bacteria of the Lachnoclostridium genus ranked top in a positive association with infiltrating CD8+ T cells (correlation coefficient = 0.38, p = 9.4 _ 10(-14)), followed by Gelidibacter (0.31, p = 1.13 _ 10(-9)), Flammeovirga (0.29, p = 1.96 _ 10(-8)) and Acinetobacter (0.28, p = 8.94 _ 10(-8)). These intratumour genera positively correlated with chemokine CXCL9, CXCL10 and CCL5 expression. The high Lachnoclostridium load significantly reduced the mortality risk (p = 0.0003). However, no statistically significant correlation was observed between intratumour Lachnoclostridium abundance and the levels of either NK, B or CD4+ T cells. CONCLUSION: Intratumour-residing gut microbiota could modulate chemokine levels and affect CD8+ T-cell infiltration, consequently influencing patient survival in cutaneous melanoma. Manipulating the intratumour gut microbiome may benefit patient outcomes for those undergoing immunotherapy.

Author Info: (1) Gansu Provincial Academy of Medical Science, Gansu Provincial Cancer Hospital, Lanzhou, 730050, China; Department of Chronic Disease Epidemiology, Yale School of Public Health,

Author Info: (1) Gansu Provincial Academy of Medical Science, Gansu Provincial Cancer Hospital, Lanzhou, 730050, China; Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT, USA. (2) Gansu Provincial Academy of Medical Science, Gansu Provincial Cancer Hospital, Lanzhou, 730050, China. (3) Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA. (4) Department of Surgery, Division of Surgical Oncology, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA. (6) Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT, USA. Electronic address: lingeng.lu@yale.edu.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.