Biomedical Informatics Commons^™

Ten Challenges And Opportunities In Computational Immuno-Oncology, Riyue Bao, Alan Hutson, Anant Madabhushi, Vanessa D Jonsson, Spencer R Rosario, Jill S Barnholtz-Sloan, Elana J Fertig, Himangi Marathe, Lyndsay Harris, Jennifer Altreuter, Qingrong Chen, James Dignam, Andrew J Gentles, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Erika Kim, Mark Long, Martin Morgan, Eytan Ruppin, David Van Valen, Hong Zhang, Natalie Vokes, Daoud Meerzaman, Song Liu, Eliezer M Van Allen, Yi Xing

Faculty, Staff and Student Publications

Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary …

Impact Of Select Actionable Genomic Alterations On Efficacy Of Neoadjuvant Immunotherapy In Resectable Non-Small Cell Lung Cancer, Nicolas Zhou, Cheuk H Leung, William N William, Annikka Weissferdt, Apar Pataer, Myrna C B Godoy, Brett W Carter, Frank V Fossella, Anne S Tsao, George R Blumenschein, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren A Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Hai T Tran, Jia Wu, Luisa M Solis Soto, Humam Kadara, Stephen G Swisher, Ara A Vaporciyan, Don L Gibbons, Heather Y Lin, J Jack Lee, John V Heymach, Marcelo V Negrao, Boris Sepesi, Tina Cascone

Faculty, Staff and Student Publications

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.

Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF …

Perioperative Chemoimmunotherapy Induces Strong Immune Responses And Long-Term Survival In Patients With Hla Class I-Deficient Non-Small Cell Lung Cancer, Marta Molina-Alejandre, Francisco Perea, Virginia Calvo, Cristina Martinez-Toledo, Ernest Nadal, Belén Sierra-Rodero, Marta Casarrubios, Joaquín Casal-Rubio, Alex Martinez-Martí, Amelia Insa, Bartomeu Massuti, Santiago Viteri, Isidoro Barneto Aranda, Delvys Rodriguez-Abreu, Javier De Castro, Joaquín Mosquera Martínez, Manuel Cobo, Ignacio I Wistuba, Edwin R Parra, Javier Martín-López, Diego Megías, Rafael Muñoz-Viana, Federico Garrido, Natalia Aptsiauri, Francisco Ruiz-Cabello, Mariano Provencio, Alberto Cruz-Bermúdez

Faculty, Staff and Student Publications

BACKGROUND: Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.

METHODS: Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data …

First-In-Human Clinical Outcomes With Ng-350a, An Anti-Cd40 Expressing Tumor-Selective Vector Designed To Remodel Immunosuppressive Tumor Microenvironments, Aung Naing, Danny Khalil, Oliver Rosen, D Ross Camidge, Tom Lillie, Rui-Ru Ji, Andrea Stacey, Matthew Thomas, Lee Rosen

Faculty, Staff and Student Publications

Background: Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.

Methods: Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 …

Cd28 Costimulation Augments Car Signaling In Nk Cells Via The Lck/Cd3Ζ/Zap70 Signaling Axis, Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, …

Novel Ox40 And 4–1bb Derived Spacers Enhance Cd30 Car Activity And Safety In Cd30 Positive Lymphoma Models, Lindsay Kua, Chee Hoe Ng, Jin Wei Tan, Hwee Ching Tan, Cheah Chen Seh, Fiona Wong, Richard Ong, Cliona M Rooney, Joel Tan, Qingfeng Chen, Ivan D Horak, Kar Wai Tan, Lionel Low

Faculty, Staff and Students Publications

The chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, has produced promising clinical efficacy with a favorable safety profile in the treatment of relapsed or refractory CD30-positive lymphomas. However, persistence of the autologous CAR-T cells was brief, and many patients relapsed a year after treatment. The lack of persistence may be attributed to the use of a wild-type immunoglobulin (Ig)G1 spacer that can associate with Fc receptors. We first identified the cysteine-rich domain (CRD) 5 of CD30 as the primary binding epitope of HRS-3 and armed with this insight, attempted to improve the HRS-3 CAR functionality …

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …

Mechanisms By Which The Intratumoral Microbiome May Potentiate Immunotherapy Response, Dalissa Negrón-Figueroa, Lauren E Colbert

Faculty, Staff and Student Publications

No abstract provided.

Inulin-Gel-Based Oral Immunotherapy Remodels The Small Intestinal Microbiome And Suppresses Food Allergy, Kai Han, Fang Xie, Olamide Animasahun, Minal Nenwani, Sho Kitamoto, Yeji Kim, May Thazin Phoo, Jin Xu, Fulei Wuchu, Kehinde Omoloja, Abhinav Achreja, Srinadh Choppara, Zhaoheng Li, Wang Gong, Young Seok Cho, Hannah Dobson, Jinsung Ahn, Xingwu Zhou, Xuehui Huang, Xinran An, Alexander Kim, Yao Xu, Qi Wu, Soo-Hong Lee, Jessica J O'Konek, Yuying Xie, Yu Leo Lei, Nobuhiko Kamada, Deepak Nagrath, James J Moon

Faculty, Staff and Student Publications

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells …

Tcellsi: A Novel Method For T Cell State Assessment And Its Applications In Immune Environment Prediction, Jing-Min Yang, Nan Zhang, Tao Luo, Mei Yang, Wen-Kang Shen, Zhen-Lin Tan, Yun Xia, Libin Zhang, Xiaobo Zhou, Qian Lei, An-Yuan Guo

Faculty, Staff and Student Publications

T cell is an indispensable component of the immune system and its multifaceted functions are shaped by the distinct T cell types and their various states. Although multiple computational models exist for predicting the abundance of diverse T cell types, tools for assessing their states to characterize their degree of resting, activation, and suppression are lacking. To address this gap, a robust and nuanced scoring tool called T cell state identifier (TCellSI) leveraging Mann-Whitney

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …

In Vivo Crispr Screens Identify Mga As An Immunotherapy Target In Triple-Negative Breast Cancer, Xu Feng, Chang Yang, Yuanjian Huang, Dan Su, Chao Wang, Lori Lyn Wilson, Ling Yin, Mengfan Tang, Siting Li, Zhen Chen, Dandan Zhu, Shimin Wang, Shengzhe Zhang, Jie Zhang, Huimin Zhang, Litong Nie, Min Huang, Jae-Il Park, Traver Hart, Dadi Jiang, Kuirong Jiang, Junjie Chen

Faculty, Staff and Student Publications

Understanding the mechanisms underlying immune evasion is crucial for developing novel anticancer modalities. To systematically uncover tumor-intrinsic genetic modulators involved in immune escape in tumor microenvironment, we performed genome-scale in vivo CRISPR screens in two syngeneic models and later expanded up to seven syngeneic models with a focused validation library. These data help us better understand tumor immune evasion and pave the way for developing effective therapeutics. Importantly, we uncovered that Mga depletion elicited an antitumor immune response and inhibited tumor growth in triple-negative breast cancer. Our findings suggest that Mga may play a role in modulating the tumor immune …

Mta-Cooperative Prmt5 Inhibitors Enhance T Cell-Mediated Antitumor Activity In Mtap-Loss Tumors, Si Chen, Jiakai Hou, Roshni Jaffery, Ashley Guerrero, Rongjie Fu, Leilei Shi, Ningbo Zheng, Ritu Bohat, Nicholas A Egan, Chengtai Yu, Sana Sharif, Yue Lu, Wei He, Shuyue Wang, Donjeta Gjuka, Everett M Stone, Pooja Anil Shah, Jordi Rodon Ahnert, Taiping Chen, Xinli Liu, Mark T Bedford, Han Xu, Weiyi Peng

Faculty, Staff and Student Publications

BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.

METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were …

Clinical Outcomes After Idecabtagene Vicleucel In Older Patients With Multiple Myeloma: A Multicenter Real-World Experience, Nilesh M Kalariya, Michelle A T Hildebrandt, Doris K Hansen, Surbhi Sidana, Jack Khouri, Christopher J Ferreri, William N Doyle, Omar Castaneda-Puglianini, Ciara L Freeman, Vanna Hovanky, Hitomi Hosoya, Leyla O Shune, Krina K Patel

Faculty, Staff and Student Publications

The safety and efficacy of chimeric antigen receptor T-cell therapy is not well described in older patients, a population that has higher frailty and comorbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (aged < 65 years) vs older (aged ≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n = 75, aged ≥65 years) were infused with ide-cel by data cutoff. In older patients (median age: 69 years; range, 65-83; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable with pivotal KarMMa study results (ORR: 73%). Median progression-free survival and overall survival in older patients were 9.1 months and 26.5 months, respectively. Grade ≥3 cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in 1% and 4% of older patients, respectively. Compared with younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (≥5 drugs; 97%), ≥4 comorbidities (69%), and organ dysfunction (35%; P < .05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.

Targeting Igf2 To Reprogram The Tumor Microenvironment For Enhanced Viro-Immunotherapy, Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Faculty, Staff and Student Publications

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. …

Identification Of Hypoxia-Alcamhigh Macrophage- Exhausted T Cell Axis In Tumor Microenvironment Remodeling For Immunotherapy Resistance, Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Faculty, Staff and Student Publications

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM

Target Engagement And Immunogenicity Of An Active Immunotherapeutic Targeting Pathological Α-Synuclein: A Phase 1 Placebo-Controlled Trial, Pepijn Eijsvogel, Pinaki Misra, Luis Concha-Marambio, Justin D Boyd, Shuang Ding, Lauren Fedor, Yueh-Ting Hsieh, Yu Shuang Sun, Madeline M Vroom, Carly M Farris, Yihua Ma, Marieke L De Kam, Igor Radanovic, Maurits F J M Vissers, Dario Mirski, Ghazal Shareghi, Mohammad Shahnawaz, Wolfgang Singer, Philip Kremer, Geert Jan Groeneveld, Hui Jing Yu, Jean-Cosme Dodart

Faculty, Staff and Student Publications

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks …

Strategies For The Development Of Metalloimmunotherapies, Xiaoqi Sun, Xingwu Zhou, Xiaoyue Shi, Omar A Abed, Xinran An, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host-microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases.

Immunoprevention Strategies For Colorectal Cancer In Lynch Syndrome Carriers, Charles M Bowen, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce …

Inferring Super-Resolution Tissue Architecture By Integrating Spatial Transcriptomics With Histology, Daiwei Zhang, Amelia Schroeder, Hanying Yan, Haochen Yang, Jian Hu, Michelle Y Y Lee, Kyung S Cho, Katalin Susztak, George X Xu, Michael D Feldman, Edward B Lee, Emma E Furth, Linghua Wang, Mingyao Li

Faculty, Staff and Student Publications

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.

Hybridizing Mechanistic Modeling And Deep Learning For Personalized Survival Prediction After Immune Checkpoint Inhibitor Immunotherapy, Joseph D Butner, Prashant Dogra, Caroline Chung, Eugene J Koay, James W Welsh, David S Hong, Vittorio Cristini, Zhihui Wang

Faculty, Staff and Student Publications

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, …

Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular …

Neoantigen-Specific Cytotoxic Tr1 Cd4 T Cells Suppress Cancer Immunotherapy, Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Naveen Sharma, Tian-Tian Liu, Vladimir Sukhov, Maria Firulyova, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Andres M Salazar, Robert Burns, Helio A Costa, Kelly D Moynihan, Yik Andy Yeung, Ivana Djuretic, Ton N Schumacher, Kathleen C F Sheehan, Marco Colonna, James P Allison, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber

Faculty, Staff and Student Publications

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified …

Chick Embryo Chorioallantoic Membrane As A Platform For Assessing The In Vivo Efficacy Of Chimeric Antigen Receptor T-Cell Therapy In Solid Tumors, Allison J Nipper, Emilie A K Warren, Kershena S Liao, Hsuan-Chen Liu, Chieko Michikawa, Caroline E Porter, Gabrielle A Wells, Mariana Villanueva, Fabio Henrique Brasil Da Costa, Ratna Veeramachaneni, Hugo Villanueva, Masataka Suzuki, Andrew G Sikora

Faculty, Staff and Student Publications

The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied …

First-In-Human Dose Escalation Trial To Evaluate The Clinical Safety And Efficacy Of An Anti-Magea1 Autologous Tcr-Transgenic T Cell Therapy In Relapsed And Refractory Solid Tumors, Martin Wermke, Tobias A W Holderried, Jason John Luke, Van K Morris, Winfried H Alsdorf, Katrin Wetzko, Borje S Andersson, Ignacio I Wistuba, Edwin R Parra, Mohammad B Hossain, Sandra Grund-Gröschke, Katrin Aslan, Arun Satelli, Anantha Marisetty, Swapna Satam, Mamta Kalra, Jens Hukelmann, M Alper Kursunel, Karine Pozo, Andreas Acs, Linus Backert, Melissa Baumeister, Sebastian Bunk, Claudia Wagner, Oliver Schoor, Ali S Mohamed, Andrea Mayer-Mokler, Norbert Hilf, Delfi Krishna, Steffen Walter, Apostolia M Tsimberidou, Cedrik M Britten

Faculty, Staff and Student Publications

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.

TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of …

Bayesian Sequential Monitoring Strategies For Trials Of Digestive Cancer Therapeutics, Guillaume Mulier, Ruitao Lin, Thomas Aparicio, Lucie Biard

Faculty, Staff and Student Publications

Background: New therapeutics in oncology have presented challenges to existing paradigms and trial designs in all phases of drug development. As a motivating example, we considered an ongoing phase II trial planned to evaluate the combination of a MET inhibitor and an anti-PD-L1 immunotherapy to treat advanced oesogastric carcinoma. The objective of the paper was to exemplify the planning of an adaptive phase II trial with novel anti-cancer agents, including prolonged observation windows and joint sequential evaluation of efficacy and toxicity.

Methods: We considered various candidate designs and computed decision rules assuming correlations between efficacy and toxicity. Simulations were conducted …

A Crisis In Clinical Research, David S Hong, Patricia Lorusso, Mario Sznol

Faculty, Staff and Student Publications

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

The Multifaceted Role Of Neutrophils In Nsclc In The Era Of Immune Checkpoint Inhibitors, Shucheng Miao, Bertha Leticia Rodriguez, Don L Gibbons

Faculty, Staff and Student Publications

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, …

Intratumoral Immune Triads Are Required For Immunotherapy-Mediated Elimination Of Solid Tumors, Gabriel Espinosa-Carrasco, Edison Chiu, Aurora Scrivo, Paul Zumbo, Asim Dave, Doron Betel, Sung Wook Kang, Hee-Jin Jang, Matthew D Hellmann, Bryan M Burt, Hyun-Sung Lee, Andrea Schietinger

Faculty, Staff and Students Publications

Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. …