Potent, Selective CARs as Potential T-Cell Therapeutics for HPV-positive Cancers

Wang, Xueyin; Sandberg, Mark L.; Martin, Aaron D.; Negri, Kathleen R; Gabrelow, Grant B.; Nampe, Daniel; Wu, Ming-Lun; McElvain, Michele; Warshaviak, Dora Toledo; Lee, Wen-Hua; Oh, Julyun; Daris, Mark; Chai, Falene; Yao, Christine; Furney, James; Pigott, Craig R.; Kamb, Alexander; Han, Xu

doi:10.1097/cji.0000000000000386

Cited by 17 publications

(21 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because the most potent, selective CARs derived from the primary (unoptimized) binder screen were only ~1 uM in the T2 assay, well below the best sub-nanomolar TCRs and CARs [17],…”

Section: Optimization Of Kras Binders Results In Higher Sensitivity B...mentioning

confidence: 99%

“…It is known that TCRs can display dangerous cross-reactivity to displayed peptides that differ by as many as 4 residues [23]. We therefore explored possible cross reactivity of peptides, identified as described previously [17], of genes expressed in adult human tissue (Supplementary Figure 4). We compared the functional response of the optimized CARs and benchmarks against 26 10mer peptides, including WT and G12D, differing in sequence from KRAS G12V at 1-4 positions.…”

Section: Optimization Of Kras Binders Results In Higher Sensitivity B...mentioning

confidence: 99%

“…Jurkat NFAT activation functional assays were conducted as previously described [15,17]. Briefly, Jurkat cells were transfected with TCR or CAR constructs using standard protocols for the Neon™ transfection system (Invitrogen, MPK5000).…”

Section: Jurkat Nfat Functional Assaymentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMCs) from healthy donors, obtained from AllCells (Alameda, California), were cultured and transduced with KRAS TCR or CAR constructs using custom lentivirus (Alstem) as previously described [15,17]. In the absence of enrichment, primary T cells were stained for TCR or CAR expression and pMHC probe binding similarly as described above for Jurkat cells.…”

Section: Primary T Cell Assaysmentioning

confidence: 99%

“…Based on these biochemical and mass spectrometry findings and the literature, we limited further efforts to G12V peptides complexed with A*11. We screened a library of random antibodies generated by induced RAG1-mediated rearrangement of heavy (H) chain gene segments in HEK293 cells, paired with a common kappa light (L) chain [15,17]. We used A*11 complexed with KRAS G12V peptides in tetrameric form as a labeled probe, followed by counter screens with pMHCs composed of A*11/wild type (WT) KRAS peptides.…”

Section: Isolated Kras G12v Pmhc Mabs Demonstrate Selectivity Over Wt...mentioning

confidence: 99%

See 4 more Smart Citations

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity

Tokatlian

Asuelime

Naradikian

et al. 2022

Cancer Research Communications

Self Cite

View full text Add to dashboard Cite

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize scFvs against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V or G12D mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs.

show abstract

“…Because the most potent, selective CARs derived from the primary (unoptimized) binder screen were only ~1 uM in the T2 assay, well below the best sub-nanomolar TCRs and CARs [17],…”

Section: Optimization Of Kras Binders Results In Higher Sensitivity B...mentioning

confidence: 99%

Section: Optimization Of Kras Binders Results In Higher Sensitivity B...mentioning

confidence: 99%

Section: Jurkat Nfat Functional Assaymentioning

confidence: 99%

Section: Primary T Cell Assaysmentioning

confidence: 99%

Section: Isolated Kras G12v Pmhc Mabs Demonstrate Selectivity Over Wt...mentioning

confidence: 99%

See 3 more Smart Citations

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity

Tokatlian

Asuelime

Naradikian

et al. 2022

Cancer Research Communications

Self Cite

View full text Add to dashboard Cite

show abstract

Final outcomes analysis of the cell product SQZ‐PBMC‐HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration

Weaver,

Iams,

Park

et al. 2024

Molecular Carcinogenesis

View full text Add to dashboard Cite

Cancer vaccines strive to induce robust, antigen‐targeted, T‐cell‐mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ‐PBMC‐HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA‐A*02+ patients. The SQZ‐PBMC‐HPV‐101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ‐PBMC‐HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre‐dose and post‐dose 4 weeks after treatment start. Biomarkers including CD8, MHC‐I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre‐ and post‐dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ‐PBMC‐HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells.

show abstract

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Ye,

Zheng,

et al. 2023

MedComm

View full text Add to dashboard Cite

Human papillomavirus (HPV) is the most prevalent sexually transmitted virus globally. Persistent high‐risk HPV infection can result in cervical precancerous lesions and cervical cancer, with 70% of cervical cancer cases associated with high‐risk types HPV16 and 18. HPV infection imposes a significant financial and psychological burden. Therefore, studying methods to eradicate HPV infection and halt the progression of precancerous lesions remains crucial. This review comprehensively explores the mechanisms underlying HPV‐related cervical lesions, including the viral life cycle, immune factors, epithelial cell malignant transformation, and host and environmental contributing factors. Additionally, we provide a comprehensive overview of treatment methods for HPV‐related cervical precancerous lesions and cervical cancer. Our focus is on immunotherapy, encompassing HPV therapeutic vaccines, immune checkpoint inhibitors, and advanced adoptive T cell therapy. Furthermore, we summarize the commonly employed drugs and other nonsurgical treatments currently utilized in clinical practice for managing HPV infection and associated cervical lesions. Gene editing technology is currently undergoing clinical research and, although not yet employed officially in clinical treatment of cervical lesions, numerous preclinical studies have substantiated its efficacy. Therefore, it holds promise as a precise treatment strategy for HPV‐related cervical lesions.

show abstract

Potent, Selective CARs as Potential T-Cell Therapeutics for HPV-positive Cancers

Abstract: Supplemental Digital Content is available in the text.

Cited by 17 publications

References 68 publications

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity

Final outcomes analysis of the cell product SQZ‐PBMC‐HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Contact Info

Product

Resources

About