Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Human Patient Samples
2.2. Cell Experiments
2.3. Generation of TILs and CAR-TILs
2.4. CAR Detection
2.5. Cytotoxicity Experiments
2.6. Mouse Experiments
2.7. Canine CAR-TIL Expansion
2.8. First-in-Dog (FIDO) Trial
2.9. Protein Analysis
2.10. Statistical Analyses of Experimental Data
2.11. Single Cell Gene Expression Analysis
2.12. RNA-Sequencing
2.13. Transcriptomic Classification
3. Results
3.1. TILs Differentially Express Chemokine Receptors and Selectins
3.2. CAR-TILs Can Kill Melanoma Cells In Vitro
3.3. CAR-TILs Can Kill Melanoma Cells In Vivo
3.4. First-in-Dog (FIDO) Trial Suggests CAR-TIL Therapy Is Safe and May Have Anti-Tumoral Activity in Tumor-Bearing Companion Dogs
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Days after Treatment | Treatment | Number of Cells/kg | CAR Expression | Tumor Size (mm) | CRP (mg/L) | WBC (109/L) | Eosinophils (109/L) | Side Effects |
---|---|---|---|---|---|---|---|---|
0 | Dose 1: CAR-TILs | 0.1 million | 70% (mRNA) | <7 | 5 | 0.3 | ||
14 | Dose 2: CAR-TILs | 10 million | 75% (mRNA) | 15 × 13 | <7 | 8.4 | 0.4 | Diarrhea that resolved after one day |
35 | 27 × 14 | <7 | 7.9 | 0.5 | ||||
63 | 35 × 29 | <7 | 7.4 | 0.4 | ||||
78 | Dose 3: CAR-TILs | 10 million | 1–7% (virus) | 42 × 24 | <7 | 7.2 | 0.6 | |
78 | IL-2 injections 30,000 IU/kg q12h | Diarrhea and vomiting, decreased appetite all grade 1 | ||||||
84 | IL-2 injections 30,000 IU/kg q12h | 36 × 22 | 58 | 10.5 | 1.3 | Eosinophilia grade 1 | ||
89 | IL-2 injections 30,000 IU/kg q12h | 34 × 24 | 51 | 23.2 | 9.7 | Eosinophilia grade 1 | ||
112 | 52 × 44 | <7 | 11.2 | |||||
133 | Euthanized due to tumor progression |
Days after Treatment | Treatment | Number of Cells/kg | CAR Expression | CRP (mg/L) | WBC (109/L) | Eosinophils (109/L) | Side Effects |
---|---|---|---|---|---|---|---|
0 | Dose 1: CAR-TILs | 0.1 million | 79% (mRNA) | <7 | 6.6 | 0.5 | |
20 | Dose 2: CAR-TILs | 10 million | 9% (virus) | <7 | 4.4 | 0.3 | |
21–24 | IL-2 injections 30,000 IU/kg q12h | Altered appetite, vomiting and diarreha all grade 1 | |||||
27–32 | IL-2 injections 30,000 IU/kg q24h | 43 | 12.9 | 2.5 | Eosinophilia, altered appetite, vomiting, diarreha and lethargy all grade 1 | ||
34 | 12 | 22.1 | 10.9 | Eosinophilia grade 1 | |||
241 | Revisit, in CR | ||||||
290 | Revisit, still in CR |
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Forsberg, E.M.V.; Riise, R.; Saellström, S.; Karlsson, J.; Alsén, S.; Bucher, V.; Hemminki, A.E.; Olofsson Bagge, R.; Ny, L.; Nilsson, L.M.; et al. Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs. Cancers 2023, 15, 648. https://doi.org/10.3390/cancers15030648
Forsberg EMV, Riise R, Saellström S, Karlsson J, Alsén S, Bucher V, Hemminki AE, Olofsson Bagge R, Ny L, Nilsson LM, et al. Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs. Cancers. 2023; 15(3):648. https://doi.org/10.3390/cancers15030648
Chicago/Turabian StyleForsberg, Elin M. V., Rebecca Riise, Sara Saellström, Joakim Karlsson, Samuel Alsén, Valentina Bucher, Akseli E. Hemminki, Roger Olofsson Bagge, Lars Ny, Lisa M. Nilsson, and et al. 2023. "Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs" Cancers 15, no. 3: 648. https://doi.org/10.3390/cancers15030648