Regression of Renal Cell Carcinoma by T Cell Receptor-engineered T Cells Targeting a Human Endogenous Retrovirus

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Sep 12

PMID 39266213

Authors

Stefan Barisic

Elizabeth M Brahmbhatt

Elena Cherkasova

Timothy T Spear

Ujjawal Savani

Stephanie Pierre

Gina M Scurti

Long Chen

Muna Igboko

Rosa Nadal

Gang Zeng

Gordon Parry

David F Stroncek

Steven Highfill

Annika V Dalheim

Robert Reger

Michael I Nishimura

Richard W Childs

Affiliations

Soon will be listed here.

Abstract

Background: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells).

Methods: We isolated a CD8 T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells.

Results: The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8 T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11 ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC.

Conclusions: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).

Citing Articles

The role and mechanism of NAT10-mediated ac4C modification in tumor development and progression.

Gu Z, Zou L, Pan X, Yu Y, Liu Y, Zhang Z MedComm (2020). 2024; 5(12):e70026.

PMID: 39640362 PMC: 11617596. DOI: 10.1002/mco2.70026.

A T cell receptor specific for an HLA-A*03:01-restricted epitope in the endogenous retrovirus ERV-K-Env exhibits limited recognition of its cognate epitope.

Grundy E, Shaw L, Wang L, Lee A, Argueta J, Powell Jr D Mob DNA. 2024; 15(1):19.

PMID: 39385229 PMC: 11462856. DOI: 10.1186/s13100-024-00333-w.

References

Zhou F, Krishnamurthy J, Wei Y, Li M, Hunt K, Johanning G . Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras. Oncoimmunology. 2015; 4(11):e1047582. PMC: 4589998. DOI: 10.1080/2162402X.2015.1047582. View

Cameron B, Gerry A, Dukes J, Harper J, Kannan V, Bianchi F . Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013; 5(197):197ra103. PMC: 6002776. DOI: 10.1126/scitranslmed.3006034. View

Smith C, Beckermann K, Bortone D, de Cubas A, Bixby L, Lee S . Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest. 2018; 128(11):4804-4820. PMC: 6205406. DOI: 10.1172/JCI121476. View

Cherkasova E, Malinzak E, Rao S, Takahashi Y, Senchenko V, Kudryavtseva A . Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene. 2011; 30(47):4697-706. PMC: 3161150. DOI: 10.1038/onc.2011.179. View

Motzer R, Tannir N, Mcdermott D, Frontera O, Melichar B, Choueiri T . Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378(14):1277-1290. PMC: 5972549. DOI: 10.1056/NEJMoa1712126. View

Nelson P, Carnegie P, Martin J, Ejtehadi H, Hooley P, Roden D . Demystified. Human endogenous retroviruses. Mol Pathol. 2003; 56(1):11-8. PMC: 1187282. DOI: 10.1136/mp.56.1.11. View

Panda A, de Cubas A, Stein M, Riedlinger G, Kra J, Mayer T . Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight. 2018; 3(16). PMC: 6141170. DOI: 10.1172/jci.insight.121522. View

Ishak C, Classon M, De Carvalho D . Deregulation of Retroelements as an Emerging Therapeutic Opportunity in Cancer. Trends Cancer. 2018; 4(8):583-597. DOI: 10.1016/j.trecan.2018.05.008. View

Cherkasova E, Scrivani C, Doh S, Weisman Q, Takahashi Y, Harashima N . Detection of an Immunogenic HERV-E Envelope with Selective Expression in Clear Cell Kidney Cancer. Cancer Res. 2016; 76(8):2177-85. PMC: 4873424. DOI: 10.1158/0008-5472.CAN-15-3139. View

10.

Chong C, Muller M, Pak H, Harnett D, Huber F, Grun D . Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes. Nat Commun. 2020; 11(1):1293. PMC: 7064602. DOI: 10.1038/s41467-020-14968-9. View

11.

Minati R, Perreault C, Thibault P . A Roadmap Toward the Definition of Actionable Tumor-Specific Antigens. Front Immunol. 2021; 11:583287. PMC: 7793940. DOI: 10.3389/fimmu.2020.583287. View

12.

Middleton D, Menchaca L, Rood H, Komerofsky R . New allele frequency database: http://www.allelefrequencies.net. Tissue Antigens. 2003; 61(5):403-7. DOI: 10.1034/j.1399-0039.2003.00062.x. View

13.

Norell H, Zhang Y, McCracken J, Martins da Palma T, Lesher A, Liu Y . CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting. Cancer Immunol Immunother. 2010; 59(6):851-62. PMC: 3736983. DOI: 10.1007/s00262-009-0810-8. View

14.

Bao W, Kojima K, Kohany O . Repbase Update, a database of repetitive elements in eukaryotic genomes. Mob DNA. 2015; 6:11. PMC: 4455052. DOI: 10.1186/s13100-015-0041-9. View

15.

Spear T, Callender G, Roszkowski J, Moxley K, Simms P, Foley K . TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother. 2016; 65(3):293-304. PMC: 4887146. DOI: 10.1007/s00262-016-1800-2. View

16.

Nagarsheth N, Norberg S, Sinkoe A, Adhikary S, Meyer T, Lack J . TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021; 27(3):419-425. PMC: 9620481. DOI: 10.1038/s41591-020-01225-1. View

17.

Kim H, Shim B, Lee S, Lee J, Lee H, Kim I . Loss of Von Hippel-Lindau () Tumor Suppressor Gene Function: -HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC). Int J Mol Sci. 2021; 22(18). PMC: 8470481. DOI: 10.3390/ijms22189795. View

18.

Rooney M, Shukla S, Wu C, Getz G, Hacohen N . Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015; 160(1-2):48-61. PMC: 4856474. DOI: 10.1016/j.cell.2014.12.033. View

19.

Kotecha R, Motzer R, Voss M . Towards individualized therapy for metastatic renal cell carcinoma. Nat Rev Clin Oncol. 2019; 16(10):621-633. DOI: 10.1038/s41571-019-0209-1. View

20.

Takahashi Y, Harashima N, Kajigaya S, Yokoyama H, Cherkasova E, McCoy J . Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest. 2008; 118(3):1099-109. PMC: 2248804. DOI: 10.1172/JCI34409. View