(UroToday.com) Dr. Gao (MD Anderson) opened the first session of the 8th Annual Leo and Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium with his talk on immunotherapy and genetic alterations that affect response to treatment. He provided an overview of tumor genomic alterations highlighting IFN gamma alteration, 9p21 loss, RNA splicing errors and FGRF3 mutation. He hypothesized that MTAP deficiency in 9p21 loss in bladder cancer would result in hypersensitivity to anti-folate agents such as pemetrexed via synthetic lethality. His team observed that treating human cell lines with 9p21 with pemetrexed resulted in increased cell death. In addition, loss of 9p21 results in MTAP loss which is involved in nucleotide synthesis and cell survival. Using MTAP as a surrogate for 9p21 loss he observed a poorer response to immunotherapy. He concluded the talk by emphasizing that 9p21 loss correlates with a “cold” tumor microenvironment, poor clinical outcomes, and resistance to immunotherapy. Therapeutic strategies targeting folate metabolism, PD1/PDL-1 pathway and adenosine pathway in bladder cancer with 9p21 loss are areas of future research.
CAR-T cells are genetically engineered T cells that target tumor antigens independent of MHC presentation and can induce tumor death.1 In hematologic malignancies, CAR-T cells have had impressive therapeutic effects which have encouraged studies in solid organ tumor malignancies, especially genitourinary tumors. 1 Dr. Nausheen (University of Kansas) reviewed advances in CAR-T cell therapy, especially in hematological malignancies and how lessons learned can be applied to solid tumors. She started by reviewing the process of CAR-T cells development using viral DNA insertion to genetically modify a patient’s T cells followed by amplification before being transfused back to the patient (diagram below). As she pointed out, the first generation of CAR T cells were developed in 1993 but it was not until 2017 that it was first approved for clinical use. There are now different constructs with five generations of CAR T therapies. 2 A challenge with disease relapse is due to antigen escape but new targets are being developed using antigens such as CD22 in lymphoma and antigen multitargeting. Other strategies include modifying antigen affinity and combining antigens with other small molecules. T cell exhaustion is also being tackled by a fourth generation of CAR T cells with “self-driving” properties. In solid tumors, there are concerns relating to on-target tumor effect given that there is no exclusive antigen on tumor cells. Several strategies being studied using SynNotch receptors by identifying two antigens to activate the CAR T cell while protecting normal tissue which has only one antigen.
Dr. Horowitz (Mount Sinai) continued the session with a discussion of using both NK and CD8 T cells in bladder cancer microenvironment to target BCG unresponsive NMIBC. He started by pointing out that NK cells lack antigen receptors, and their activation is regulated by the collective strength of inhibitory and activating signals. He explained that both HLA-E and NKG2A serve as inhibitory checkpoints for CD8 T Cells. He highlighted that blocking the NKG2 A receptor enhances tumor immunity by enhancing and rescuing NK and CD8 T cells function.3 In addition, HLA-E is strongly enhanced in BCG unresponsive tumors. Lastly, he discussed that adaptive immune resistance can be seen with NK inhibitory pathways.
Expanding on NK cells, Dr. Rafei (MD Anderson) highlighted a new generation of engineered NK cells as vehicles for CAR T cell therapy in their efforts to reduce cost and increase access to treatment. These are advantageous and great candidates in that they do not cause graft versus host disease even in the allogeneic setting, there is no need for antigen priming, they can be inhibitory or activated, found primarily in the blood, part of the innate immune system and reduces the risk of disease relapse. Based on TCGA data, CD70 can be used as a pan cancer antigen including in solid organ tumors. Importantly, CD70 has low expression in normal tissues. ARGX-110, a human monoclonal antibody targeting CD70 has been tested in multiple trials with promising results. Her lab is studying Burkitt lymphoma in CD70+ mouse models and have shown impressive results with a CAR-NK construct. In addition, she reported high cytotoxicity with CAR T cell treatment in kidney cancer preclinical models without dysregulated or autonomous growth with no on target off tumor effect.
Closing the session, Dr. Akhavan (University of Kansas) introduced new opportunities to overcome obstacles in designing CAR-T cells for use within the bladder cancer space. He discussed the challenges in solid organ tumors including CAR T tumor infiltration, overcoming inhibitory molecules and cells in the tumor microenvironment and most importantly tumor antigen heterogeneity. The latter may be tackled by using CAR T cells targeting EGFR, HER2, IL13Rα2 over-expression in urothelial cancers as shown in TCGA data. Other targets currently in clinical trials include CD19, CD19+CD22, CD19 + CD20, CD22, CD20, ROR1R, CD4, CD7, CD38, CD30, and BCMA. 2 He highlighted a recent Phase I trial (NCT03089203) in metastatic castration-resistant prostate cancer using CAR T cells armored with a dominant-negative TGF-β receptor, an inhibitory factor.4 In total 13 patients received therapy; 3 patients had ≥30% PSA reduction including one patient with >98% reduction. However, there were 5 patients who developed grade ≥2 cytokine release syndrome including one patient succumbing to it. CAR T failure was seen by tumor microenvironment inhibitory molecules upregulation. Results are promising and efforts is needed to explore approaches to mitigate the inhibitory tumor microenvironment. Additionally, he reports that his lab has shown an enhanced potential for combined radiation with CAR T therapy. He reports promising results using in vivo glioma models treated with 10Gy and IL13Rα2 CAR T cells. Although CAR T cell therapy is still in infancy in solid organ tumors especially in genitourinary tumors, the future is promising.
Presented By:
- Jianjun Gao MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
- Ahmad Nausheen MD, Medical Director BMT Survivorship Program, Medical Oncologist at The University of Kansas Cancer Center
- Amir Horowitz PhD, Assistant Professor of Oncological Sciences and a member of the Precision Immunology Institute and the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai
- Hind Rafei MD, Assistant Professor, Stem Cell Transplant and Cellular Therapy, The University of Texas MD Anderson Cancer Center
- David Akhavan MD, PhD, Assistant Professor, Radiation Oncology, The University of Kansas Medical Center
Written by: Valentina Grajales MD, MS, Urologic Oncology Fellow, Twitter: @ValGraj, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022
References:
2. Zhao, Lijun and Cao J Yu. Engineered T Cell Therapy for Cancer in the Clinic. Front Immunol. 2019 Oct 11;10:2250. doi: 10.3389/fimmu.2019.02250. eCollection 2019.
3. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018 Dec 13;175(7):1731-1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29. PMID: 30503213; PMCID: PMC6292840.
4. Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, Hwang WT, Lal P, Carpenter EL, Maude SL, Plesa G, Vapiwala N, Chew A, Moniak M, Sebro RA, Farwell MD, Marshall A, Gilmore J, Lledo L, Dengel K, Church SE, Hether TD, Xu J, Gohil M, Buckingham TH, Yee SS, Gonzalez VE, Kulikovskaya I, Chen F, Tian L, Tien K, Gladney W, Nobles CL, Raymond HE; Prostate Cancer Cellular Therapy Program Investigators, Hexner EO, Siegel DL, Bushman FD, June CH, Fraietta JA, Haas NB. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022 Apr;28(4):724-734. doi: 10.1038/s41591-022-01726-1. Epub 2022 Mar 21. PMID: 35314843.