Biomedical Informatics Commons^™

Enhancement Of Immunotherapies In Head And Neck Cancers Using Biomaterial-Based Treatment Strategies, Gemalene M Sunga, Jeffrey Hartgerink, Andrew G Sikora, Simon Young

Faculty, Staff and Student Publications

Head and neck squamous cell carcinoma (HNSCC) is a challenging disease to treat because of typically late-stage diagnoses and tumor formation in difficult-to-treat areas, sensitive to aggressive or invasive treatments. To date, HNSCC treatments have been limited to surgery, radiotherapy, and chemotherapy, which may have significant morbidity and often lead to long-lasting side effects. The development of immunotherapies has revolutionized cancer treatment by providing a promising alternative to standard-of-care therapies. However, single-agent immunotherapy has been only modestly effective in the treatment of various cancers, including HNSCC, with most patients receiving no overall benefit or increased survival. In addition, single-agent immunotherapy's …

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival In Patients With Head And Neck Cancer, Hannah Y Chen, Weilu Zhao, Shorook Na'ara, Frederico O Gleber-Netto, Tongxin Xie, Shahrukh Ali, Zachary M Thompson, Jane Buell, Haleigh Stafford, Priyadharsini Nagarajan, Michael Davies, Michael K Wong, Michael R Migden, Padmanee Sharma, Jeffrey N Myers, Neil D Gross, Moran Amit

Faculty, Staff and Student Publications

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen.

METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 …

Society For Immunotherapy Of Cancer (Sitc) Clinical Practice Guideline On Immunotherapy For The Treatment Of Gynecologic Cancer, Mary L Disis, Sarah F Adams, Jyoti Bajpai, Marcus O Butler, Tyler Curiel, Shelley A Dodt, Laura Doherty, Leisha A Emens, Claire F Friedman, Margaret Gatti-Mays, Melissa A Geller, Amir Jazaeri, Veena S John, Katherine C Kurnit, John B Liao, Haider Mahdi, Anne Mills, Emese Zsiros, Kunle Odunsi

Faculty, Staff and Student Publications

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, …

Pan-Cancer T Cell Atlas Links A Cellular Stress Response State To Immunotherapy Resistance, Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Davis R Ingram, Krupa Thakkar, Jiang-Jiang Qin, Minghao Dang, Xiuning Le, Can Hu, Qing Deng, Ansam Sinjab, Pravesh Gupta, Ruiping Wang, Dapeng Hao, Fuduan Peng, Xinmiao Yan, Yunhe Liu, Shumei Song, Shaojun Zhang, John V Heymach, Alexandre Reuben, Yasir Y Elamin, Melissa P Pizzi, Yang Lu, Rossana Lazcano, Jian Hu, Mingyao Li, Michael Curran, Andrew Futreal, Anirban Maitra, Amir A Jazaeri, Jaffer A Ajani, Charles Swanton, Xiang-Dong Cheng, Hussein A Abbas, Maura Gillison, Krishna Bhat, Alexander J Lazar, Michael Green, Kevin Litchfield, Humam Kadara, Cassian Yee, Linghua Wang

Faculty, Staff and Student Publications

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with …

Efficacy And Safety Of Nivolumab Plus Ipilimumab Vs Nivolumab Alone For Treatment Of Recurrent Or Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Phase 2 Checkmate 714 Randomized Clinical Trial, Kevin J Harrington, Robert L Ferris, Maura Gillison, Makoto Tahara, Athanasios Argiris, Jérôme Fayette, Michael Schenker, Åse Bratland, John W T Walker, Peter Grell, Caroline Even, Christine H Chung, Rebecca Redman, Alexandre Coutte, Sébastien Salas, Cliona Grant, Sergio De Azevedo, Denis Soulières, Aaron R Hansen, Li Wei, Tariq Aziz Khan, Karen Miller-Moslin, Mustimbo Roberts, Robert Haddad

Faculty, Staff and Student Publications

IMPORTANCE: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

OBJECTIVE: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN.

DESIGN, SETTING, AND PARTICIPANTS: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from …

Correction Of T-Cell Repertoire And Autoimmune Diabetes In Nod Mice By Non-Myeloablative T-Cell Depleted Allogeneic Hsct, Rakefet Sidlik Muskatel, Bar Nathansohn-Levi, Shlomit Reich-Zeliger, Michal Mark, Liat Stoler-Barak, Chava Rosen, Irit Milman-Krentsis, Esther Bachar Lustig, Robert Pete Gale, Nir Friedman, Yair Reisner

Faculty, Staff and Student Publications

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated …

Immunologic Predictors For Clinical Responses During Immune Checkpoint Blockade In Patients With Myelodysplastic Syndromes, Sung-Eun Lee, Feng Wang, Maison Grefe, Abel Trujillo-Ocampo, Wilfredo Ruiz-Vasquez, Koichi Takahashi, Hussein A Abbas, Pamella Borges, Dinler Amaral Antunes, Gheath Al-Atrash, Naval Daver, Jeffrey J Molldrem, Andrew Futreal, Guillermo Garcia-Manero, Jin S Im

Faculty, Staff and Student Publications

PURPOSE: The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA).

EXPERIMENTAL DESIGN: Peripheral blood samples from 55 patients with MDS were assessed for immune subsets, T-cell receptor (TCR) repertoire, mutations in 295 acute myeloid leukemia (AML)/MDS-related genes, and immune-related gene expression profiling before and after the first treatment.

RESULTS: Clinical responders treated with IMT ± HMA but not HMA alone showed a significant expansion of central memory (CM) CD8+ T cells, diverse TCRβ repertoire pretreatment with increased clonality and …

Five-Year Follow-Up Of Zuma-1 Supports The Curative Potential Of Axicabtagene Ciloleucel In Refractory Large B-Cell Lymphoma, Sattva S Neelapu, Caron A Jacobson, Armin Ghobadi, David B Miklos, Lazaros J Lekakis, Olalekan O Oluwole, Yi Lin, Ira Braunschweig, Brian T Hill, John M Timmerman, Abhinav Deol, Patrick M Reagan, Patrick Stiff, Ian W Flinn, Umar Farooq, Andre H Goy, Peter A Mcsweeney, Javier Munoz, Tanya Siddiqi, Julio C Chavez, Alex F Herrera, Nancy L Bartlett, Adrian A Bot, Rhine R Shen, Jinghui Dong, Kanwarjit Singh, Harry Miao, Jenny J Kim, Yan Zheng, Frederick L Locke

Faculty, Staff and Student Publications

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% …

Brexucabtagene Autoleucel For Relapsed Or Refractory Mantle Cell Lymphoma In Standard-Of-Care Practice: Results From The Us Lymphoma Car T Consortium, Yucai Wang, Preetesh Jain, Frederick L Locke, Matthew J Maurer, Matthew J Frank, Javier L Munoz, Saurabh Dahiya, Amer M Beitinjaneh, Miriam T Jacobs, Joseph P Mcguirk, Julie M Vose, Andre Goy, Charalambos Andreadis, Brian T Hill, Kathleen A Dorritie, Olalekan O Oluwole, Abhinav Deol, Jonas Paludo, Bijal Shah, Trent Wang, Rahul Banerjee, David B Miklos, Aaron P Rapoport, Lazaros Lekakis, Armin Ghobadi, Sattva S Neelapu, Yi Lin, Michael L Wang, Michael D Jain

Faculty, Staff and Student Publications

Purpose: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.

Patients and methods: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Clinical Outcomes Of Immunotherapy Continued Beyond Radiographic Disease Progression In Older Adult Patients With Advanced Non-Small Cell Lung Cancer, Eric K Singhi, Frank Mott, Michelle Worst, Cheuk Hong Leung, J Jack Lee, Brett Carter, Carolyn J Presley, John V Heymach, Mehmet Altan

Faculty, Staff and Student Publications

Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged ≥70 years) with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond radiographic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

Phase I Trial Of Autologous Rna-Electroporated Cmet-Directed Car T Cells Administered Intravenously In Patients With Melanoma And Breast Carcinoma, Payal D Shah, Alexander C Huang, Xiaowei Xu, Robert Orlowski, Ravi K Amaravadi, Lynn M Schuchter, Paul Zhang, Julia Tchou, Tina Matlawski, Amanda Cervini, Joanne Shea, Joan Gilmore, Lester Lledo, Karen Dengel, Amy Marshall, E John Wherry, Gerald P Linette, Andrea Brennan, Vanessa Gonzalez, Irina Kulikovskaya, Simon F Lacey, Gabriela Plesa, Carl H June, Robert H Vonderheide, Tara C Mitchell

Faculty, Staff and Student Publications

PURPOSE: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.

EXPERIMENTAL DESIGN: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.

RESULTS: Mean age was …

Development And Validation Of A Patient-Reported Outcome Measure To Assess Symptom Burden After Chimeric Antigen Receptor T-Cell Therapy, Xin Shelley Wang, Samer A Srour, Tito Mendoza, Meagan Whisenant, Ishwaria Subbiah, Elizabeth Gonzalez, Mona Kamal, Shu-En Shen, Charles Cleeland, Partow Kebriaei, Katayoun Rezvani, Sattva Neelapu, Sairah Ahmed, Elizabeth Shpall

Faculty, Staff and Student Publications

This cross-sectional study aimed to develop and validate a patient-reported outcomes (PROs) assessment tool to assess symptom burden and daily functioning in patients after chimeric antigen receptor (CAR) T-cell therapy, the MD Anderson Symptom Inventory (MDASI-CAR). The items were generated based on literature review, content elicitation interviews with patients, and clinician's review. The patients completed the MDASI core and module, single-item quality-of-life (QoL) measure and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29). The psychometric validation analysis was based on the acceptability after item reduction process. The final 10 MDASI-CAR module items included tremors, fever/chills, headache, balance, dizziness, attention, difficulty speaking, coughing, …

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Unlocking The Promise Of Systemic Sting Agonist For Cancer Immunotherapy, Xiaoqi Sun, Xingwu Zhou, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING …

Pirtobrutinib And Venetoclax Combination Overcomes Resistance To Targeted And Chimeric Antigen Receptor T-Cell Therapy In Aggressive Mantle Cell Lymphoma, Yang Liu, Fangfang Yan, Vivian Changying Jiang, Yijing Li, Yuxuan Che, Joseph Mcintosh, Alexa Jordan, Ian Hou, Lei Nie, Jingling Jin, Wei Wang, Heng-Huan Lee, Yixin Yao, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

Mapping The Functional Interactions At The Tumor-Immune Checkpoint Interface, Behnaz Bozorgui, Elisabeth K Kong, Augustin Luna, Anil Korkut

Faculty, Staff and Student Publications

The interactions between tumor intrinsic processes and immune checkpoints can mediate immune evasion by cancer cells and responses to immunotherapy. It is, however, challenging to identify functional interactions due to the prohibitively complex molecular landscape of the tumor-immune interfaces. We address this challenge with a statistical analysis framework, immuno-oncology gene interaction maps (ImogiMap). ImogiMap quantifies and statistically validates tumor-immune checkpoint interactions based on their co-associations with immune-associated phenotypes. The outcome is a catalog of tumor-immune checkpoint interaction maps for diverse immune-associated phenotypes. Applications of ImogiMap recapitulate the interaction of SERPINB9 and immune checkpoints with interferon gamma (IFNγ) expression. Our analyses …

The "Great Debate" At Melanoma Bridge 2022, Naples, December 1st-3rd, 2022, Paolo A Ascierto, Christian Blank, Alexander M Eggermont, Claus Garbe, Jeffrey E Gershenwald, Omid Hamid, Axel Hauschild, Jason J Luke, Janice M Mehnert, Jeffrey A Sosman, Hussein A Tawbi, Mario Mandalà, Alessandro Testori, Corrado Caracò, Iman Osman, Igor Puzanov

Faculty, Staff and Student Publications

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge …

The Abscopal Effect In Patients With Cancer Receiving Immunotherapy, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for …

Immune Checkpoint Therapy-Current Perspectives And Future Directions, Padmanee Sharma, Sangeeta Goswami, Deblina Raychaudhuri, Bilal A Siddiqui, Pratishtha Singh, Ashwat Nagarajan, Jielin Liu, Sumit K Subudhi, Candice Poon, Kristal L Gant, Shelley M Herbrich, Swetha Anandhan, Shajedul Islam, Moran Amit, Gayathri Anandappa, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Integrative Clinical And Genomic Characterization Of Mtap-Deficient Metastatic Urothelial Cancer, Omar Alhalabi, Yueting Zhu, Ameer Hamza, Wei Qiao, Yiyun Lin, Raymond M Wang, Amishi Y Shah, Matthew T Campbell, Vijaykumar Holla, Ashish Kamat, Wei-Lien Wang, Jennifer Wang, Jianfeng Chen, Jieru Meng, Miao Zhang, Jolanta Bondaruk, Mark Titus, Giannicola Genovese, Bogdan A Czerniak, Kenna R Shaw, Funda Meric-Bernstam, Charles C Guo, Christopher J Logothetis, Arlene Siefker-Radtke, Pavlos Msaouel, Linghua Wang, Jiyan Liu, Jianjun Gao

Faculty, Staff and Student Publications

Deficiency of MTAP (MTAPdef) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAPdef mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAPdef (n = 48) than for MTAP-proficient (MTAPprof; n = 145) patients (75% vs 55.2%; p = 0.02). MTAPdef was associated with poor prognosis (median overall …

Letter To The Editor: Quality Criteria For Computational Models Predicting Individual Outcomes In Car-T Cell Therapy, Anna M Mc Laughlin, Cassian Yee

Faculty, Staff and Student Publications

No abstract provided.

A Non-Antibiotic-Disrupted Gut Microbiome Is Associated With Clinical Responses To Cd19-Car-T Cell Cancer Immunotherapy, Christoph K Stein-Thoeringer, Neeraj Y Saini, Eli Zamir, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Matthias A Fante, Sabine Schmidt, Eiko Hayase, Tomo Hayase, Roman Rohrbach, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Rogier Gaiser, Matthias Edinger, Daniel Wolff, Martin Heidenreich, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Raphael E Steiner, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Michael L Wang, Joel Turner, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Peter Dreger, Anita Schmitt, Carsten Müller-Tidow, Frederick L Locke, Marco L Davila, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Hendrik Poeck, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Michael D Jain, Robert R Jenq, Eran Elinav

Faculty, Staff and Student Publications

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals …

Advancing Car T Cell Therapy Through The Use Of Multidimensional Omics Data, Jingwen Yang, Yamei Chen, Ying Jing, Michael R Green, Leng Han

Faculty, Staff and Student Publications

Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, …

Axicabtagene Ciloleucel In Relapsed Or Refractory Large B-Cell Lymphoma Patients In Complete Metabolic Response, Andrew P Jallouk, Sushanth Gouni, Jason Westin, Lei Feng, Haleigh Mistry, Raphael E Steiner, Jinsu James, Mansoor Noorani, Sandra Horowitz, Nahum Puebla-Osorio, Luis E Fayad, Swaminathan P Iyer, Misha Hawkins, Christopher R Flowers, Sairah Ahmed, Loretta J Nastoupil, Partow Kebriaei, Elizabeth J Shpall, Sattva S Neelapu, Yago Nieto, Paolo Strati

Faculty, Staff and Student Publications

No abstract provided.

T-Cell Receptor Repertoire Sequencing In The Era Of Cancer Immunotherapy, Meredith L Frank, Kaylene Lu, Can Erdogan, Yi Han, Jian Hu, Tao Wang, John V Heymach, Jianjun Zhang, Alexandre Reuben

Faculty, Staff and Student Publications

T cells are integral components of the adaptive immune system, and their responses are mediated by unique T-cell receptors (TCR) that recognize specific antigens from a variety of biological contexts. As a result, analyzing the T-cell repertoire offers a better understanding of immune responses and of diseases like cancer. Next-generation sequencing technologies have greatly enabled the high-throughput analysis of the TCR repertoire. On the basis of our extensive experience in the field from the past decade, we provide an overview of TCR sequencing, from the initial library preparation steps to sequencing and analysis methods and finally to functional validation techniques. …

Microbiome Influencers Of Checkpoint Blockade-Associated Toxicity, Yinghong Wang, Robert R Jenq, Jennifer A Wargo, Stephanie S Watowich

Faculty, Staff and Student Publications

Immunotherapy has greatly improved cancer outcomes, yet variability in response and off-target tissue damage can occur with these treatments, including immune checkpoint inhibitors (ICIs). Multiple lines of evidence indicate the host microbiome influences ICI response and risk of immune-related adverse events (irAEs). As the microbiome is modifiable, these advances indicate the potential to manipulate microbiome components to increase ICI success. We discuss microbiome features associated with ICI response, with focus on bacterial taxa and potential immune mechanisms involved in irAEs, and the overall goal of driving novel approaches to manipulate the microbiome to improve ICI efficacy while avoiding irAE risk.

Immune And Pathologic Responses In Patients With Localized Prostate Cancer Who Received Daratumumab (Anti-Cd38) Or Edicotinib (Csf-1r Inhibitor), Bilal A Siddiqui, Brian F Chapin, Sonali Jindal, Fei Duan, Sreyashi Basu, Shalini S Yadav, Ai-Di Gu, Alexsandra B Espejo, Michelle Kinder, Curtis A Pettaway, John F Ward, Rebecca S S Tidwell, Patricia Troncoso, Paul G Corn, Christopher J Logothetis, Roland Knoblauch, Natalie Hutnick, Marco Gottardis, Charles G Drake, Padmanee Sharma, Sumit K Subudhi

Faculty, Staff and Student Publications

BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses.

HYPOTHESIS: Daratumumab or edicotinib will be safe and …

Surgical Results Of The Lung Cancer Mutation Consortium 3 Trial: A Phase Ii Multicenter Single-Arm Study To Investigate The Efficacy And Safety Of Atezolizumab As Neoadjuvant Therapy In Patients With Stages Ib-Select Iiib Resectable Non-Small Cell Lung Cancer, Valerie W Rusch, Alan Nicholas, G Alexander Patterson, Salama N Waqar, Eric M Toloza, Eric B Haura, Dan J Raz, Karen L Reckamp, Robert E Merritt, Dwight H Owen, David J Finley, Ciaran J Mcnamee, Justin D Blasberg, Edward B Garon, John D Mitchell, Robert C Doebele, Frank Baciewicz, Misako Nagasaka, Harvey I Pass, Katja Schulze, Ann Johnson, Paul A Bunn, Bruce E Johnson, Mark G Kris, David J Kwiatkowski, Ignacio I Wistuba, Jamie E Chaft, David P Carbone, Jay M Lee

Faculty, Staff and Student Publications

Objective: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.

Methods: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was …