John Lee's Pioneering Research at UCLA: Advancing Immunotherapy and Unraveling Cancer Mechanisms

John K. Lee, M.D., Ph.D., a distinguished medical oncologist at UCLA, is at the forefront of cancer research, particularly in the areas of advanced prostate and bladder cancers, and Ewing Sarcoma. His work encompasses both understanding the fundamental mechanisms driving these diseases and translating those findings into innovative therapeutic strategies. This article delves into Dr. Lee's research, highlighting his significant contributions to immunotherapy, his investigations into the genetic underpinnings of cancer, and his commitment to developing novel treatments.

Expertise and Research Focus

Dr. Lee's expertise lies in developing immunotherapies for genitourinary cancers and deciphering the complex genetic interactions that underlie cancer initiation and progression. His research interests include:

Understanding the interaction of oncogenic events in the initiation and progression of prostate and bladder cancers.
Identifying antigens as targets to develop antibody and cell-based immunotherapies.
Targeting Myc and AR in castration-resistant prostate cancer.
Engineering advanced, personalized immunotherapies to treat prostate and bladder cancer.
Investigating approaches to boost immune response against stubborn or immunologically "cold" solid tumors.
Evaluating novel applications of antibody-drug combination therapies for prostate cancer.
Deciphering genotype-phenotype relationships involved in cancer development and progression.

Innovations in Preclinical Cancer Modeling

Dr. Lee has innovated a preclinical approach to rapidly generate diverse cancer subtypes from stem/progenitor-enriched primary epithelial cells. This groundbreaking method enables interrogation of genotype-phenotype relationships at scale using massively parallel single-cell sequencing, providing unprecedented insights into cancer biology. Li S, Wong A, Sun H*, Bhatia V, Javier G, Jana S, Montgomery RB, Wright JL, Lam H-M, Hsieh AC, Faltas BM, Haffner MC, Lee JK developed Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations. bioRxiv. 2023 Apr 14.

Clinical Translation: CAR-T Cell Therapies

Dr. Lee's studies have directly led to the development of early-phase clinical trials investigating two CAR-T cell therapies for metastatic castration-resistant prostate cancer and small cell neuroendocrine prostate cancer. These trials represent a significant step forward in the application of immunotherapy to treat these aggressive cancers.

Immunotherapy Advancements for Ewing Sarcoma

Ewing sarcoma (ES) is an aggressive and rare type of pediatric cancer involving bones and their surrounding soft tissue with a grim 5-year survival rate of 15-30%. Dr. Lee is also focusing his research efforts on Ewing Sarcoma, an aggressive pediatric cancer. Recognizing the limitations of conventional treatments, he is developing a new targeted immune-based treatment for advanced Ewing sarcoma. Dr. Lee has developed a chimeric antigen receptor (CAR) T cell therapy against a cell surface protein known as STEAP1. STEAP1, or six transmembrane epithelial antigen of the prostate 1, is present in >90% of ES tumors and is highly expressed on the surface of cancer cells, with limited expression in normal tissues. Additionally, it is implicated in cancer proliferation and invasion, making it an ideal candidate for immunotherapy in ES.

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Enhancing CAR-T Cell Therapy with IL-18

Dr. Lee proposes to further increase the cancer-killing ability of STEAP1 CAR T cells by engineering them to secrete a molecule called interleukin-18 (IL-18). IL-18 is a proinflammatory cytokine that broadens anti-tumor immunity by enhancing the killing activity of CAR T cells and bridging the gap between innate and adaptive immune responses. By armoring STEAP1 CAR T cells with IL-18, Dr. Lee will test the effectiveness and safety of his IL-18 armored STEAP1 CAR T cells in newly created models of ES that more closely resemble the advanced disease found in children.

Promising Preclinical Results

Dr. Lee and his team continue to make promising progress toward advancing their IL-18 armored STEAP1 CAR T cell therapy for children with relapsed or refractory Ewing sarcoma. In new studies using mice with human immune systems, both the standard and IL-18 armored CAR T cells caused rapid tumor shrinkage, demonstrating strong anti-tumor activity. Additionally, early safety testing in mice engineered to express the human STEAP1 protein showed no signs of general toxicity. The team has also begun using new imaging tools to examine how CAR T cells interact with tumor cells in the tumor microenvironment, which will help clarify how IL-18 enhances their function in solid tumors like Ewing sarcoma. In parallel, clinical-grade manufacturing of the therapy is moving forward, keeping the program on track for future clinical testing.

Ongoing Progress and Future Directions

One year into the Acceleration Initiative Award, Dr. Lee and his team have made meaningful progress in advancing their IL-18 armored STEAP1 CAR T cell therapy for Ewing sarcoma, continuing progress toward their goal of moving this treatment to a first-in-human clinical trial. In lab experiments, they have confirmed that their enhanced CAR T cells, which include the immune-stimulating molecule IL-18, demonstrate more effective tumor-killing activity compared to unmodified or non-armored CAR T cells. Early safety studies in mouse models also show encouraging results, with no signs of added toxicity observed thus far. The team has now established and begun testing the therapy in new, highly specialized mice that mimic the human immune system to better understand how the treatment might perform in children. Additional safety testing is underway using alternative tumor models that progress more slowly, providing a longer window to detect potential side effects.

In the first 6 months of the award, Dr. Lee and his team have made considerable progress in investigating IL-18 armored STEAP1 CAR T cell therapy for safety and efficacy in preclinical studies. The team has completed experiments to show that their CAR T cell therapy demonstrates rapid and improved killing of Ewing sarcoma across multiple rechallenges over time. Additionally, they have obtained their first set of mice bearing human immune systems and have characterized these mice to ensure that they can appropriately support human immune cells. In upcoming experiments, the team will inject these mice with human Ewing sarcoma cells to determine how well tumors develop and spread. They will then use these new mouse models to test their IL-18 armored STEAP1 CAR T cells and determine barriers to effectiveness of this treatment. Additionally, Dr. Lee and his team have taken initial steps towards their goal of quickly moving this therapeutic approach to a first-in-human phase I clinical trial by the end of the award period, including working with companies to support the manufacturing of IL-18 armored STEAP1 CAR T cells for commercial use.

Selected Publications

Dr. Lee's research has been published in several high-impact journals. Some notable publications include:

DeLucia DC, Cardillo T, Ang L, Labrecque MP, Zhang A, Hopkins JE, Gil da Costa RM, Corey E, True LD, Haffner MC, Schweizer MT, Morrissey C, Nelson PS, Lee JK. Regulation of CEACAM5 and therapeutic efficacy of an anti-CEACAM5-SN-38 antibody-drug conjugate in neuroendocrine prostate cancer. Clin Cancer Res. 2021 Feb 1;27(3):759-774. This study explores the role of CEACAM5 in neuroendocrine prostate cancer and the therapeutic potential of an antibody-drug conjugate targeting this protein.
Mao Z, Nesterenko PA, McLaughlin J, Deng W, Sojo GB, Cheng D, Noguchi M, Chour W, DeLucia DC, Finton KA, Qin Y, Obusan MB, Tran W, Wang L, Bangayan NJ, Ta L, Chen CC, Seet CS, Crooks GM, Phillips JW, Heath JR, Strong RK, Lee JK, Wohlschlegel JA, Witte ON. Combined physical and in silico immunopeptidomic profiling of the cancer antigen prostatic acid phosphatase reveals peptide targets enabling cognate TCR isolation. Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2203410119. This research focuses on identifying peptide targets from prostatic acid phosphatase, a cancer antigen, to enable the isolation of cognate T cell receptors.
Bhatia V, Kamat NV, Pariva TE*, Wu L, Tsao A, Sasaki K, Sun H, Javier G, Nutt S, Coleman I, Hitchcock L, Zhang A, Rudoy D, Gulati R, Patel RA, Roudier MP, True LD, Srivastava S, Morrissey CM, Haffner MC, Nelson PS, Priceman SJ, Ishihara J#, Lee JK#. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun. 2023 Apr 11;14(1):2041. This publication details the development of a STEAP1-targeted CAR T cell therapy, enhanced with tumor-localized IL-12, for the treatment of advanced prostate cancer.
Xu AM, Xu AM, Chour W, DeLucia DC, Su Y, Pavlovitch-Bedzyk AJP, Ng R, Rasheed Y, Davis M, Lee JK, Heath JR. Entropic analysis of antigen-specific CDR3 domains identifies essential binding motifs shared by CDR3s with different antigen specificities. Cell Syst. 2023 Apr 19;14(4):273-284.e5. This study employs entropic analysis to identify essential binding motifs in antigen-specific CDR3 domains, which are crucial for T cell recognition of antigens.

Patient Experiences and Care Philosophy

Patients consistently praise Dr. Lee for his exceptional care, clear communication, and compassionate approach. He is described as attentive, patient, and knowledgeable, taking the time to explain complex diagnoses and treatment plans in a way that is easy to understand. Patients also appreciate his willingness to answer questions and address their concerns, fostering a sense of trust and confidence.

Some patient testimonials include:

"Best provider. treats me with care and allows for me to ask questions."
"Dr. Lee pronounced me as cured from my prostate cancer after over 20 years."
"Clear. Direct. Explained all the appropriate details of the situation. Did not feel rushed at all."
"Dr Lee was fabulous he explained everything very professionally and at the same time very kind. Very On time. Helpful. Focused conversation and general discussion. Dr Lee is relaxed and focuses on my questions. He was very patient and asked me important questions regarding my health. Great doctor. Friendly. Caring."
"my doctors thru my entire treatment have been compassionate, understanding, knowledgeable and assessible during my treatment process. I a m extremely grateful ?? and will never forget my experiences here at UCLA with them!"
"Dr. Exceptional. Dr Lee was on time and he listened. The appointment with Dr John K. Lee was excellent!! He was very professional and completely prepared. He explained my cancer diagnosis step by step and recommended the next steps for my treatment. I have tremendous confidence in Dr. He was very solicitous about my well being, and answered all my questions. This was the first time meeting Dr. Lee. Dr. Lee is very attentive. 3 month check. I am doing well so we didn't have much to go over. Dr. In this follow up video visit, Dr Lee was most professional and approachable. My doctor is highly professional and kind."

These testimonials highlight Dr. Lee's commitment to providing patient-centered care, characterized by empathy, clear communication, and a focus on individual needs.

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