Biological Phenomena, Cell Phenomena, and Immunity Commons^™

The Path Forward For T Cell Engagers In Patients With Prostate Cancer, Sumit K. Subudhi, Bilal A. Siddiqui, Kevin K. Zarrabi, William K. Kelly, Charles G. Drake

Department of Medical Oncology Faculty Papers

T cell engagers (TCEs) recruit T cells to the tumor microenvironment (TME) to induce antitumor immune responses. TCEs have demonstrated promising clinical responses in patients with metastatic castration-resistant prostate cancer and have advanced into phase 3 clinical trials. Here we provide an overview of the mechanisms of action of TCEs, including both CD3-targeted and CD28-targeted agents, and review the clinical development of these agents for prostate cancer. We propose a path forward for TCEs in prostate cancer, in which innovative clinical trials will facilitate a biological understanding of mechanisms of efficacy and toxicity to inform: (1) development of predictive biomarkers …

International Consensus Guidelines For The Conduct And Reporting Of Car T-Cell Clinical Trials In Aml, Swati Naik, Richard Aplenc, Susanne H C Baumeister, Marco Becilli, Anand S Bhagwat, Challice L Bonifant, Lihua E Budde, Christopher D Chien, Kevin J Curran, Anthony F Daniyan, Alexandra Dreyzin, Rebecca A Gardner, Sara Ghorashian, Stephen Gottschalk, Laquisa C Hill, M Eric Kohler, Adam Lamble, Franco Locatelli, Maksim Mamonkin, Bilal Omer, Jae H Park, Concetta Quintarelli, Benedetta Rambaldi, Rebecca M Richards, David A Sallman, Tim Sauer, Nirali N Shah, Marion Subklewe, Corinne Summers, Sarah K Tasian, Naomi Taylor, Sarah Tettamanti, Michael R Verneris, M Paulina Velasquez, Saar I Gill

Faculty, Staff and Students Publications

Early clinical experience with the use of chimeric antigen receptor (CAR) T-cell therapies for patients with acute myeloid leukemia (AML) has been beset by high rates of toxicities and low rates of response. We convened an international workshop with the goal of bringing investigators in the field of AML-directed CAR T-cell therapy together to facilitate discussion of challenges and to brainstorm potential solutions. Based on discussions at the workshop, it was evident that (1) treating and targeting AML with CAR T cells is associated with unique clinical challenges, and (2) variability in clinical trial design, definitions of toxicities, correlative data …

Infection After Cd19 Chimeric Antigen Receptor T-Cell Therapy For Large B-Cell Lymphoma: Real-World Analysis From Cibmtr, Kitsada Wudhikarn, Megan M Herr, Min Chen, Michael J Martens, John H Baird, Lohith Gowda, Hemalatha G Rangarajan, Muhammad Bilal Abid, Mohamed A Kharfan-Dabaja, Kirsten M Williams, Siddhartha Ganguly, Jo-Anne H Young, Akshay Sharma, Giancarlo Fatobene, Tania Jain, Christopher G Kanakry, Dipenkumar Modi, Natalie S Grover, Baheyeldin Salem, Marjorie Vieira Batista, Paschalis Vergidis, Dwight E Yin, Amer M Beitinjaneh, Amar H Kelkar, Taiga Nishihori, Jennifer Holter Chakrabarty, Usama Gergis, Melody Smith, Zeinab El Boghdadly, Christopher E Dandoy, Hemant S Murthy, Anna R Huppler, Miguel-Angel Perales, Roy F Chemaly, Joshua A Hill, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, …

Real-World Outcomes Of Infections Following Tisagenlecleucel In Patients With B-Cell All: A Cibmtr Analysis, Hemalatha G Rangarajan, Prakash Satwani, Megan M Herr, Min Chen, Michael J Martens, Kitsada Wudhikarn, Samuel John, Vanessa A Fabrizio, Emily M Hsieh, Amar H Kelkar, Erin Doherty, David I Marks, Olle Ringden, Brian Friend, Matthew S Kelly, Nosha Farhadfar, Tim Prestidge, Nasheed M Hossain, Hongtao Liu, Shahrukh Hashmi, Dipenkumar Modi, Lena E Winestone, Zeinab El Boghdadly, Hemant S Murthy, Miguel-Angel Perales, Roy F Chemaly, Christopher E Dandoy, Joshua A Hill, Anna Huppler, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. …

Peritoneal Immunosurgery: Immunotherapy Augmented Surgery For The Treatment Of Peritoneal Cancers, Ada I Ozcan, Arianexys Aquino López, Mary K Mckenna, Malcolm K Brenner, Alastair M Thompson

Faculty, Staff and Students Publications

Peritoneal malignancy often indicates disruptions in multiple physiological systems resulting from widespread cancer. The heterogenous origin and dynamic nature of peritoneal cancer make it difficult to treat with standard approaches that fit into guidelines. We describe how successful treatment should address the underlying pathology, the systemic response to surgical treatments and target the immune perturbations that facilitate the establishment and propagation of this multifaceted disease.

Endoglin-Directed Car T Cells Comprehensively Target Tumors In Advanced Sarcomas, Harrison R Berger, Malina Maharana, Jeneffer Mirabal, Lyazat Kurenbekova, Alberto Delaidelli, Atreyi Dasgupta, Ahmed Z Gad, Mohamed F Sheha, Sybrina S Kerr, Ada I Ozcan, Jessica S Morris, Angela M Major, M John Hicks, Mary K Mckenna, Ben K Seon, Matthew L Baker, Poul H Sorensen, Meenakshi Hegde, Jason T Yustein, Nabil Ahmed, Sujith K Joseph

Faculty, Staff and Students Publications

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their …

Tumor Microenvironment Governs The Prognostic Landscape Of Immunotherapy For Head And Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis, Priyan Bhattacharya, Alban J Linnenbach, Andrew P. South, Ubaldo E. Martinez-Outshoorn, Joseph M. Curry, Jennifer M. Johnson, Larry A. Harshyne, Mỹ G. Mahoney, Adam J. Luginbuhl, Rajanikanth Vadigepalli

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly …

Combined Systemic Immunotherapy And Intrathecal Dexamethasone In Febrile Infection Related Epilepsy Syndrome, Kristen S Fisher, Alexander Ankar, Jon Cokley, Eyal Muscal, James J Riviello, Yi-Chen Lai

Faculty, Staff and Students Publications

Febrile infection related epilepsy syndrome (FIRES) is a rare presentation of refractory status epilepticus with immune dysregulation as a potential pathologic mechanism. Despite promising results from second-line immunomodulators, approximately 30% remain refractory to treatment. We describe two children with FIRES who were unable to wean from anesthetic infusions with immunomodulatory treatment and subsequently received concurrent intrathecal dexamethasone and anakinra/tocilizumab as escalation of therapy. Following the initiation of this combined regimen, anesthetic infusions were decreased while maintaining seizure freedom. These cases demonstrate proof of principle that a multi-modal approach may be beneficial and should be considered in the treatment of FIRES.

Depletion Of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy, Joseph Rupert, Alexes Daquinag, Yongmei Yu, Yulin Dai, Zhongming Zhao, Mikhail G Kolonin

Faculty, Staff and Student Publications

This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.

Development Of A Ripk1 Degrader To Enhance Antitumor Immunity, Xin Yu, Dong Lu, Xiaoli Qi, Rishi Ram Paudel, Hanfeng Lin, Bryan L Holloman, Feng Jin, Longyong Xu, Lang Ding, Weiyi Peng, Meng C Wang, Xi Chen, Jin Wang

Faculty, Staff and Students Publications

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports …

Tumor-Associated Antigen Prediction Using A Single-Sample Gene Expression State Inference Algorithm, Xinpei Yi, Hongwei Zhao, Shunjie Hu, Liangqing Dong, Yongchao Dou, Jing Li, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

We developed a Bayesian-based algorithm to infer gene expression states in individual samples and incorporated it into a workflow to identify tumor-associated antigens (TAAs) across 33 cancer types using RNA sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA). Our analysis identified 212 candidate TAAs, with 78 validated in independent RNA-seq datasets spanning seven cancer types. Eighteen of these TAAs were further corroborated by proteomics data, including 10 linked to liver cancer. We predicted that 38 peptides derived from these 10 TAAs would bind strongly to HLA-A02, the most common HLA allele. Experimental validation confirmed …

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 …

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 …

Human Platelet Lysate Enhances In Vivo Activity Of Car-Vδ2 T Cells By Reducing Cellular Senescence And Apoptosis, Feiyan Mo, Chiou-Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin, Norihiro Watanabe

Faculty, Staff and Students Publications

BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.

METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet …

The Saga Of E Faecium, Rishika Prasad, Robert R Jenq

Faculty, Staff and Student Publications

An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.

Embracing Cancer Complexity: Hallmarks Of Systemic Disease, Charles Swanton, Elsa Bernard, Chris Abbosh, Fabrice André, Johan Auwerx, Allan Balmain, Dafna Bar-Sagi, René Bernards, Susan Bullman, James Degregori, Catherine Elliott, Ayelet Erez, Gerard Evan, Mark A Febbraio, Andrés Hidalgo, Mariam Jamal-Hanjani, Johanna A Joyce, Matthew Kaiser, Katja Lamia, Jason W Locasale, Sherene Loi, Ilaria Malanchi, Miriam Merad, Kathryn Musgrave, Ketan J Patel, Sergio Quezada, Jennifer A Wargo, Ashani Weeraratna, Eileen White, Frank Winkler, John N Wood, Karen H Vousden, Douglas Hanahan

Faculty, Staff and Student Publications

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism …

Targeting Innate Immunity In Glioma Therapy, Andrew G Gillard, Dong Ho Shin, Lethan A Hampton, Andres Lopez-Rivas, Akhila Parthasarathy, Juan Fueyo, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Currently, there is a lack of effective therapies for the majority of glioblastomas (GBMs), the most common and malignant primary brain tumor. While immunotherapies have shown promise in treating various types of cancers, they have had limited success in improving the overall survival of GBM patients. Therefore, advancing GBM treatment requires a deeper understanding of the molecular and cellular mechanisms that cause resistance to immunotherapy. Further insights into the innate immune response are crucial for developing more potent treatments for brain tumors. Our review provides a brief overview of innate immunity. In addition, we provide a discussion of current therapies …

Localization, Tissue Biology, And T Cell State — Implications For Cancer Immunotherapy, Jason M Schenkel, Kristen E Pauken

Faculty, Staff and Student Publications

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this …

Circulating Tumor Dna Monitoring On Chemo-Immunotherapy For Risk Stratification In Advanced Non-Small Cell Lung Cancer, Bruna Pellini, Russell W Madison, Merrida A Childress, Shoshana T Miller, Ole Gjoerup, Jason Cheng, Richard S P Huang, Michael Krainock, Pratyush Gupta, Wei Zou, David S Shames, Solomon Moshkevich, Marcus Ballinger, Minetta C Liu, Amanda Young, Minu K Srivastava, Geoffrey R Oxnard, Mark A Socinski

Faculty, Staff and Student Publications

PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor …

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome, Melissa R Hines, Tristan E Knight, Kevin O Mcnerney, Mark B Leick, Tania Jain, Sairah Ahmed, Matthew J Frigault, Joshua A Hill, Michael D Jain, William T Johnson, Yi Lin, Kris M Mahadeo, Gabriela M Maron, Rebecca A Marsh, Sattva S Neelapu, Sarah Nikiforow, Amanda K Ombrello, Nirav N Shah, Aimee C Talleur, David Turicek, Anant Vatsayan, Sandy W Wong, Marcela V Maus, Krishna V Komanduri, Nancy Berliner, Jan-Inge Henter, Miguel-Angel Perales, Noelle V Frey, David T Teachey, Matthew J Frank, Nirali N Shah

Faculty, Staff and Student Publications

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal …

A Novel Integrated Approach To Predicting Cancer Immunotherapy Efficacy, Ruihan Luo, Jacqueline Chyr, Jianguo Wen, Yanfei Wang, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint …

Immune Profiling Of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration In Mice, Maria Chen, Boram Kim, Maria I Jarvis, Samantha Fleury, Shuyun Deng, Shirin Nouraein, Susan Butler, Sangsin Lee, Courtney Chambers, H Courtney Hodges, Jerzy O Szablowski, Junghae Suh, Omid Veiseh

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector …

Apoptosis Of Hematopoietic Stem Cells Contributes To Bone Marrow Suppression Following Chimeric Antigen Receptor T Cell Therapy, Jay A Read, Rayne H Rouce, Feiyan Mo, Maksim Mamonkin, Katherine Y King

Faculty, Staff and Students Publications

Background: CAR-T therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from release of pro-inflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias and those with the most severe CRS also have the greatest delay in full marrow recovery. While an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown.

Objective: To test our hypothesis that delayed bone marrow recovery following CAR-T …

Kras-Mutant Lung Cancer: Targeting Molecular And Immunologic Pathways, Therapeutic Advantages And Restrictions, Nastaran Karimi, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and …

Technology Meets Tils: Deciphering T Cell Function In The -Omics Era, William H Hudson, Andreas Wieland

Faculty, Staff and Students Publications

T cells are at the centerstage of cancer immunology due to their ability to recognize mutations within tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms such as single-cell RNA-sequencing and high-dimensional flow cytometry has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells, both within single tumors, across tumor types, and among cancer patients. Here, we discuss the opportunities and challenges of studying the complex tumor microenvironment with …

Feasibility And Preclinical Efficacy Of Cd7-Unedited Cd7 Car T Cells For T Cell Malignancies, Norihiro Watanabe, Feiyan Mo, Rong Zheng, Royce Ma, Vanesa C Bray, Dayenne G Van Leeuwen, Juntima Sritabal-Ramirez, Hongxiang Hu, Sha Wang, Birju Mehta, Madhuwanti Srinivasan, Lauren D Scherer, Huimin Zhang, Sachin G Thakkar, Laquisa C Hill, Helen E Heslop, Chonghui Cheng, Malcolm K Brenner, Maksim Mamonkin

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the …

Next-Generation Ctla-4 Targeting Molecules And Combination Therapy: Promising Strategies For Improving Cancer Immunotherapy, Nils-Petter Rudqvist, Manushak Avagyan, Dhan Chand

Faculty, Staff and Student Publications

Radiation therapy and anti-CTLA-4 combination therapy can induce meaningful responses in some patients. Adding CD40 may provide additional benefit. Next-generation anti-CTLA-4 antibodies, such as botensilimab, are showing promise in clinical trials. Combining botensilimab with RT and/or CD40 agonist may offer additional benefits for challenging tumor types.

Deciphering The Role Of Qpctl In Glioma Progression And Cancer Immunotherapy, Yu'e Liu, Shaojuan Lu, Yihong Sun, Fei Wang, Shibo Yu, Xi Chen, Lei-Lei Wu, Hui Yang, Yufeng Shi, Kaijun Zhao

Faculty, Staff and Students Publications

BACKGROUND: Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration …

Emerging Challenges To Cellular Therapy Of Cancer, Premal D Lulla, Malcolm Brenner

Faculty, Staff and Students Publications

Cellular immunotherapy of cancer in the form of chimeric antigen receptor-modified T-cell therapy has become a standard treatment for lymphoid and more recently plasma cell malignancies. Although their successes in these cancers represent a breakthrough for adoptive cell therapy, there are several challenges to their continued growth in the field of cancer medicine. In this review, we discuss the progress made thus far toward achieving "off-the-shelf" accessibility of cell therapies that has the potential to greatly offset the costs associated with the current practice of making patient-specific products. We also review the innovations under investigation that attempt to make cellular …

Engineering Naturally Occurring Cd7- T Cells For The Immunotherapy Of Hematological Malignancies, Abdullah Freiwan, Jaquelyn T Zoine, Jeremy Chase Crawford, Abishek Vaidya, Stefan A Schattgen, Jacquelyn A Myers, Sagar L Patil, Mahsa Khanlari, Hiroto Inaba, Jeffery M Klco, Charles G Mullighan, Giedre Krenciute, Peter J Chockley, Swati Naik, Deanna M Langfitt, Maksim Mamonkin, Esther A Obeng, Paul G Thomas, Stephen Gottschalk, M Paulina Velasquez

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- …