Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Strategies for Manipulating T Cells in Cancer Immunotherapy

  • Lee, Hyang-Mi (College of Pharmacy, Dongduk Women's University)
  • Received : 2021.12.02
  • Accepted : 2022.02.08
  • Published : 2022.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

T cells are attractive targets for the development of immunotherapy to treat cancer due to their biological features, capacity of cytotoxicity, and antigen-specific binding of receptors. Novel strategies that can modulate T cell functions or receptor reactivity provide effective therapies, including checkpoint inhibitor, bispecific antibody, and adoptive transfer of T cells transduced with tumor antigen-specific receptors. T cell-based therapies have presented successful pre-clinical/clinical outcomes despite their common immune-related adverse effects. Ongoing studies will allow us to advance current T cell therapies and develop innovative personalized T cell therapies. This review summarizes immunotherapeutic approaches with a focus on T cells. Anti-cancer T cell therapies are also discussed regarding their biological perspectives, efficacy, toxicity, challenges, and opportunities.

Keywords

Acknowledgement

This work was supported by a research fund (2021-05574) from Dongduk Women's University.

References

  1. Ansell, S. M., Lesokhin, A. M., Borrello, I., Halwani, A., Scott, E. C., Gutierrez, M., Schuster, S. J., Millenson, M. M., Cattry, D., Freeman, G. J., Rodig, S. J., Chapuy, B., Ligon, A. H., Zhu, L., Grosso, J. F., Kim, S. Y., Timmerman, J. M., Shipp, M. A. and Armand, P. (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311-319. https://doi.org/10.1056/NEJMoa1411087
  2. Aung, P. P., Liu, Y. C., Ballester, L. Y., Robbins, P. F., Rosenberg, S. A. and Lee, C. C. (2014) Expression of New York esophageal squamous cell carcinoma-1 in primary and metastatic melanoma. Hum. Pathol. 45, 259-267. https://doi.org/10.1016/j.humpath.2013.05.029
  3. Bendell, J. C., Fong, L., Stein, M. N., Beer, T. M., Ross, A., Gao, X., Weitzman, A., Austin, R., Ganti, V., Law, C., Lemon, B., Wesche, H. and De Bono, J. S. (2020) First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 38, 5552. https://doi.org/10.1200/jco.2020.38.15_suppl.5552
  4. Bielamowicz, K., Fousek, K., Byrd, T. T., Samaha, H., Mukherjee, M., Aware, N., Wu, M. F., Orange, J. S., Sumazin, P., Man, T. K., Joseph, S. K., Hegde, M. and Ahmed, N. (2018) Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. NeuroOncol. 20, 506-518.
  5. Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., Bartido, S., Stefanski, J., Taylor, C., Olszewska, M., Borquez-Ojeda, O., Qu, J., Wasielewska, T., He, Q., Bernal, Y., Rijo, I. V., Hedvat, C., Kobos, R., Curran, K., Steinherz, P., Jurcic, J., Rosenblat, T., Maslak, P., Frattini, M. and Sadelain, M. (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38. https://doi.org/10.1126/scitranslmed.3005930
  6. Brocker, T. (2000) Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 96, 1999-2001. https://doi.org/10.1182/blood.v96.5.1999
  7. Brudno, J. N. and Kochenderfer, J. N. (2016) Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321-3330. https://doi.org/10.1182/blood-2016-04-703751
  8. Bubenik, J. (2003) Tumour MHC class I downregulation and immunotherapy (review). Oncol. Rep. 10, 2005-2008.
  9. Campbell, C. E., Kuriyan, N. P., Rackley, R. R., Caulfield, M. J., Tubbs, R., Finke, J. and Williams, B. R. (1998) Constitutive expression of the Wilms tumor suppressor gene (WT1) in renal cell carcinoma. Int. J. Cancer 78, 182-188. https://doi.org/10.1002/(SICI)1097-0215(19981005)78:2<182::AID-IJC11>3.0.CO;2-D
  10. Carpenter, R. O., Evbuomwan, M. O., Pittaluga, S., Rose, J. J., Raffeld, M., Yang, S., Gress, R. E., Hakim, F. T. and Kochenderfer, J. N. (2013) B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048-2060. https://doi.org/10.1158/1078-0432.CCR-12-2422
  11. Carreno, B. M. and Collins, M. (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol. 20, 29-53. https://doi.org/10.1146/annurev.immunol.20.091101.091806
  12. Chandran, S. S. and Klebanoff, C. A. (2019) T cell receptor-based cancer immunotherapy: emerging efficacy and pathways of resistance. Immunol. Rev. 290, 127-147. https://doi.org/10.1111/imr.12772
  13. Chen, D. S. and Mellman, I. (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1-10. https://doi.org/10.1016/j.immuni.2013.07.012
  14. Chen, R., Zinzani, P. L., Lee, H. J., Armand, P., Johnson, N. A., Brice, P., Radford, J., Ribrag, V., Molin, D., Vassilakopoulos, T. P., Tomita, A., von Tresckow, B., Shipp, M. A., Lin, J., Kim, E., Nahar, A., Balakumaran, A. and Moskowitz, C. H. (2019) Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 134, 1144-1153.
  15. Chow, M. T., Moller, A. and Smyth, M. J. (2012) Inflammation and immune surveillance in cancer. Semin. Cancer Biol. 22, 23-32. https://doi.org/10.1016/j.semcancer.2011.12.004
  16. Cohen, E. E. W., Soulieres, D., Le Tourneau, C., Dinis, J., Licitra, L., Ahn, M. J., Soria, A., Machiels, J. P., Mach, N., Mehra, R., Burtness, B., Zhang, P., Cheng, J., Swaby, R. F. and Harrington, K. J.; KEYNOTE-040 investigators (2019) Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393, 156-167. https://doi.org/10.1016/S0140-6736(18)31999-8
  17. Correnti, C. E., Laszlo, G. S., de van der Schueren, W. J, Godwin, C. D., Bandaranayake, A., Busch, M. A., Gudgeon, C. J., Bates, O. M., Olson, J. M., Mehlin, C. and Walter, R. B. (2018) Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 costimulation. Leukemia 32, 1239-1243. https://doi.org/10.1038/s41375-018-0014-3
  18. Costa, L. J., Wong, S. W., Bermudez, A., de la Rubia, J., Mateos, M., Ocio, E. M., Rodriguez-Otero, P., San-Miguel, J., Li, S., Sarmiento, R., Lardelli, P., Gaudy, A., Boss, I., Kelly, L. M., Burgess, M. R., Hege, K. and Bensinger, W. I. (2019) First clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): interim results of a phase 1 multicenter trial. Blood 134(Supplement_1), 143. https://doi.org/10.1182/blood-2019-122895
  19. D'Angelo, S. P., Melchiori, L., Merchant, M. S., Bernstein, D., Glod, J., Kaplan, R., Grupp, S., Tap, W. D., Chagin, K., Binder, G. K., Basu, S., Lowther, D. E., Wang, R., Bath, N., Tipping, A., Betts, G., Ramachandran, I., Navenot, J. M., Zhang, H., Wells, D. K., Van Winkle, E., Kari, G., Trivedi, T., Holdich, T., Pandite, L., Amado, R. and Mackall, C. L. (2018) Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259) T cells in synovial sarcoma. Cancer Discov. 8, 944-957. https://doi.org/10.1158/2159-8290.CD-17-1417
  20. Daver, N., Alotaibi, A. S., Bucklein, V. and Subklewe, M. (2021) T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments. Leukemia 35, 1843-1863. https://doi.org/10.1038/s41375-021-01253-x
  21. Decker, W. K. and Safdar, A. (2009) Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley's legacy revisited. Cytokine Growth Factor Rev. 20, 271-281. https://doi.org/10.1016/j.cytogfr.2009.07.004
  22. D'Ippolito, E., Schober, K., Nauerth, M. and Busch, D. H. (2019) T cell engineering for adoptive T cell therapy: safety and receptor avidity. Cancer Immunol. Immunother. 68, 1701-1712. https://doi.org/10.1007/s00262-019-02395-9
  23. Fecci, P. E., Ochiai, H., Mitchell, D. A., Grossi, P. M., Sweeney, A. E., Archer, G. E., Cummings, T., Allison, J. P., Bigner, D. D. and Sampson, J. H. (2007) Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin. Cancer Res. 13, 2158-2167. https://doi.org/10.1158/1078-0432.CCR-06-2070
  24. Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., Worden, F., Saba, N. F., Iglesias Docampo, L. C., Haddad, R., Rordorf, T., Kiyota, N., Tahara, M., Monga, M., Lynch, M., Geese, W. J., Kopit, J., Shaw, J. W. and Gillison, M. L. (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856-1867. https://doi.org/10.1056/NEJMoa1602252
  25. Garrido, F., Aptsiauri, N., Doorduijn, E. M., Garcia Lora, A. M. and van Hall, T. (2016) The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr. Opin. Immunol. 39, 44-51. https://doi.org/10.1016/j.coi.2015.12.007
  26. Ghorashian, S., Kramer, A. M., Onuoha, S., Wright, G., Bartram, J., Richardson, R., Albon, S. J., Casanovas-Company, J., Castro, F., Popova, B., Villanueva, K., Yeung, J., Vetharoy, W., Guvenel, A., Wawrzyniecka, P. A., Mekkaoui, L., Cheung, G. W., Pinner, D., Chu, J., Lucchini, G., Silva, J., Ciocarlie, O., Lazareva, A., Inglott, S., Gilmour, K. C., Ahsan, G., Ferrari, M., Manzoor, S., Champion, K., Brooks, T., Lopes, A., Hackshaw, A., Farzaneh, F., Chiesa, R., Rao, K., Bonney, D., Samarasinghe, S., Goulden, N., Vora, A., Veys, P., Hough, R., Wynn, R., Pule, M. A. and Amrolia, P. J. (2019) Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408-1414. https://doi.org/10.1038/s41591-019-0549-5
  27. Gilboa, E. (1999) The makings of a tumor rejection antigen. Immunity 11, 263-270. https://doi.org/10.1016/S1074-7613(00)80101-6
  28. Gong, J., Chehrazi-Raffle, A., Reddi, S. and Salgia, R. (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. Immunother. Cancer 6, 8.
  29. Green, E. W., Bunse, L., Bozza, M., Sanghvi, K. and Platten, M. (2019) TCR validation toward gene therapy for cancer. Methods Enzymol. 629, 419-441. https://doi.org/10.1016/bs.mie.2019.10.010
  30. Grosso, J. F. and Jure-Kunkel, M. N. (2013) CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 13, 5.
  31. Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., Milone, M. C., Levine, B. L. and June, C. H. (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509-1518. https://doi.org/10.1056/NEJMoa1215134
  32. Halliday, G. M., Patel, A., Hunt, M. J., Tefany, F. J. and Barnetson, R. S. (1995) Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells. World J. Surg. 19, 352-358. https://doi.org/10.1007/BF00299157
  33. Hargadon, K. M., Johnson, C. E. and Williams, C. J. (2018) Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 62, 29-39. https://doi.org/10.1016/j.intimp.2018.06.001
  34. Harrison, S. J., Minnema, M. C., Lee, H. C., Spencer, A., Kapoor, P., Madduri, D., Larsen, J., Ailawadhi, S., Kaufman, J. L., Raab, M. S., Hari, P., Iida, S., Vij, R., Davies, F. E., Lesley, R., Upreti, V. V., Yang, Z., Sharma, A., Minella, A. and Lentzsch, S. (2020) A phase 1 first in human (FIH) study of AMG 701, an anti-B-cell maturation antigen (BCMA) half-life extended (HLE) BiTE® (bispecific T-cell engager) molecule, in relapsed/refractory (RR) multiple myeloma (MM). Blood 136, 28-29.
  35. Herbst, R. S., Baas, P., Kim, D. W., Felip, E., Perez-Gracia, J. L., Han, J. Y., Molina, J., Kim, J. H., Arvis, C. D., Ahn, M. J., Majem, M., Fidler, M. J., de Castro, G., Garrido, M., Lubiniecki, G. M., Shentu, Y., Im, E., Dolled-Filhart, M. and Garon, E. B. (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540-1550. https://doi.org/10.1016/s0140-6736(15)01281-7
  36. Hilal, T. and Prasad, V. (2018) Eliminating MRD - FDA approval of blinatumomab for B-ALL in complete remission. Nat. Rev. Clin. Oncol. 15, 727-728. https://doi.org/10.1038/s41571-018-0087-y
  37. Hirano, F., Kaneko, K., Tamura, H., Dong, H., Wang, S., Ichikawa, M., Rietz, C., Flies, D. B., Lau, J. S., Zhu, G., Tamada, K. and Chen, L. (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65, 1089-1096. https://doi.org/10.1158/0008-5472.1089.65.3
  38. Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M. T., Shankar, S., Chen, T. C., Korman, A., Allison, J. P. and Dranoff, G. (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl. Acad. Sci. U.S.A. 100, 4712-4717. https://doi.org/10.1073/pnas.0830997100
  39. Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., Akerley, W., van den Eertwegh, A. J., Lutzky, J., Lorigan, P., Vaubel, J. M., Linette, G. P., Hogg, D., Ottensmeier, C. H., Lebbe, C., Peschel, C., Quirt, I., Clark, J. I., Wolchok, J. D., Weber, J. S., Tian, J., Yellin, M. J., Nichol, G. M., Hoos, A. and Urba, W. J. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723. https://doi.org/10.1056/NEJMoa1003466
  40. Hoffmann, M. M. and Slansky, J. E. (2020) T-cell receptor affinity in the age of cancer immunotherapy. Mol. Carcinog. 59, 862-870. https://doi.org/10.1002/mc.23212
  41. Huang, J., Brameshuber, M., Zeng, X., Xie, J., Li, Q. J., Chien, Y. H., Valitutti, S. and Davis, M. M. (2013) A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells. Immunity 39, 846-857. https://doi.org/10.1016/j.immuni.2013.08.036
  42. Huang, L. Q., Brasseur, F., Serrano, A., De Plaen, E., van der Bruggen, P., Boon, T. and Van Pel, A. (1999) Cytolytic T lymphocytes recognize an antigen encoded by MAGE-A10 on a human melanoma. J. Immunol. 162, 6849-6854. https://doi.org/10.4049/jimmunol.162.11.6849
  43. Hummel, H. D., Kufer, P., Grullich, C., Seggewiss-Bernhardt, R., Deschler-Baier, B., Chatterjee, M., Goebeler, M. E., Miller, K., de Santis, M., Loidl, W., Dittrich, C., Buck, A., Lapa, C., Thurner, A., Wittemer-Rump, S., Koca, G., Boix, O., Docke, W. D., Finnern, R., Kusi, H., Ajavon-Hartmann, A., Stienen, S., Sayehli, C. M., Polat, B. and Bargou, R. C. (2021) Pasotuxizumab, a BiTE(®) immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings. Immunotherapy 13, 125-141. https://doi.org/10.2217/imt-2020-0256
  44. Hung, C. F., Xu, X., Li, L., Ma, Y., Jin, Q., Viley, A., Allen, C., Natarajan, P., Shivakumar, R., Peshwa, M. V. and Emens, L. A. (2018) Development of anti-human mesothelin-targeted chimeric antigen receptor messenger RNA-transfected peripheral blood lymphocytes for ovarian cancer therapy. Hum. Gene Ther. 29, 614-625. https://doi.org/10.1089/hum.2017.080
  45. Imai, C., Mihara, K., Andreansky, M., Nicholson, I. C., Pui, C. H., Geiger, T. L. and Campana, D. (2004) Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676-684. https://doi.org/10.1038/sj.leu.2403302
  46. Ishiguro, T., Sano, Y., Komatsu, S. I., Kamata-Sakurai, M., Kaneko, A., Kinoshita, Y., Shiraiwa, H., Azuma, Y., Tsunenari, T., Kayukawa, Y., Sonobe, Y., Ono, N., Sakata, K., Fujii, T., Miyazaki, Y., Noguchi, M., Endo, M., Harada, A., Frings, W., Fujii, E., Nanba, E., Narita, A., Sakamoto, A., Wakabayashi, T., Konishi, H., Segawa, H., Igawa, T., Tsushima, T., Mutoh, H., Nishito, Y., Takahashi, M., Stewart, L., ElGabry, E., Kawabe, Y., Ishigai, M., Chiba, S., Aoki, M., Hattori, K. and Nezu, J. (2017) An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors. Sci. Transl. Med. 9, eaal4291. https://doi.org/10.1126/scitranslmed.aal4291
  47. Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T. and Minato, N. (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. U.S.A. 99, 12293-12297. https://doi.org/10.1073/pnas.192461099
  48. Karapetyan, A. R., Chaipan, C., Winkelbach, K., Wimberger, S., Jeong, J. S., Joshi, B., Stein, R. B., Underwood, D., Castle, J. C., van Dijk, M. and Seibert, V. (2019) TCR fingerprinting and off-target peptide identification. Front. Immunol. 10, 2501. https://doi.org/10.3389/fimmu.2019.02501
  49. Klinger, M., Benjamin, J., Kischel, R., Stienen, S. and Zugmaier, G. (2016) Harnessing T cells to fight cancer with BiTE(R) antibody constructs--past developments and future directions. Immunol. Rev. 270, 193-208. https://doi.org/10.1111/imr.12393
  50. Klinger, M., Zugmaier, G., Nagele, V., Goebeler, M. E., Brandl, C., Stelljes, M., Lassmann, H., von Stackelberg, A., Bargou, R. C. and Kufer, P. (2020) Adhesion of T cells to endothelial cells facilitates blinatumomab-associated neurologic adverse events. Cancer Res. 80, 91-101. https://doi.org/10.1158/0008-5472.can-19-1131
  51. Kontermann, R. E. and Brinkmann, U. (2015) Bispecific antibodies. Drug Discov. Today 20, 838-847. https://doi.org/10.1016/j.drudis.2015.02.008
  52. Kumar, V., Chaudhary, N., Garg, M., Floudas, C. S., Soni, P. and Chandra, A. B. (2017) Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front. Pharmacol. 8, 49. https://doi.org/10.3389/fphar.2017.00049
  53. Kuwana, Y., Asakura, Y., Utsunomiya, N., Nakanishi, M., Arata, Y., Itoh, S., Nagase, F. and Kurosawa, Y. (1987) Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem. Biophys. Res. Commun. 149, 960-968. https://doi.org/10.1016/0006-291X(87)90502-X
  54. Leach, D. R., Krummel, M. F. and Allison, J. P. (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-1736. https://doi.org/10.1126/science.271.5256.1734
  55. Lee, L., Wang, R. F., Wang, X., Mixon, A., Johnson, B. E., Rosenberg, S. A. and Schrump, D. S. (1999) NY-ESO-1 may be a potential target for lung cancer immunotherapy. Cancer J. Sci. Am. 5, 20-25.
  56. Liu, Y. and Zheng, P. (2020) Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol. Sci. 41, 4-12. https://doi.org/10.1016/j.tips.2019.11.003
  57. Loffler, A., Kufer, P., Lutterbuse, R., Zettl, F., Daniel, P. T., Schwenkenbecher, J. M., Riethmuller, G., Dorken, B. and Bargou, R. C. (2000) A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 95, 2098-2103. https://doi.org/10.1182/blood.v95.6.2098
  58. Lorenczewski, G., Friedrich, M., Kischel, R., Dahlhoff, C., Anlahr, J., Balazs, M., Rock, D., Boyle, M. C., Goldstein, R., Coxon, A. and Chapman-Arvedson, T. (2017) Generation of a half-life extended anti-CD19 BiTE® antibody construct compatible with once-weekly dosing for treatment of CD19-positive malignancies. Blood 130, 2815.
  59. Lu, Y., Parker, L., Lu, T., Zheng, Z., Yao, X., Robbins, P. F., van der Bruggen, P., Klebanoff, C. A., Hinrichs, C. S., Goff, S., Sherry, R., Kammula, U., Yang, J. C. and Rosenberg, S. A. (2015) A Phase I study of an HLA-DPB1*0401-restricted T cell receptor targeting MAGE-A3 for patients with metastatic cancers. J. Immunother. Cancer 3, P158. https://doi.org/10.1186/2051-1426-3-S2-P158
  60. Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., Nagaraja, S., Granja, J., de Bourcy, C. F. A., Majzner, R., Satpathy, A. T., Quake, S. R., Monje, M., Chang, H. Y. and Mackall, C. L. (2019) c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293-300. https://doi.org/10.1038/s41586-019-1805-z
  61. Maher, J., Brentjens, R. J., Gunset, G., Riviere, I. and Sadelain, M. (2002) Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat. Biotechnol. 20, 70-75. https://doi.org/10.1038/nbt0102-70
  62. Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., Rietberg, S. P., Linde, M. H., Xu, P., Rota, C., Sotillo, E., Labanieh, L., Lee, D. W., Orentas, R. J., Dimitrov, D. S., Zhu, Z., Croix, B. S., Delaidelli, A., Sekunova, A., Bonvini, E., Mitra, S. S., Quezado, M. M., Majeti, R., Monje, M., Sorensen, P. H. B., Maris, J. M. and Mackall, C. L. (2019) CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin. Cancer Res. 25, 2560-2574. https://doi.org/10.1158/1078-0432.ccr-18-0432
  63. Malik-Chaudhry, H. K., Prabhakar, K., Ugamraj, H. S., Boudreau, A. A., Buelow, B., Dang, K., Davison, L. M., Harris, K. E., Jorgensen, B., Ogana, H., Pham, D., Schellenberger, U., Van Schooten, W., Buelow, R., Iyer, S., Trinklein, N. D. and Rangaswamy, U. S. (2021) TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL. mAbs 13, 1890411. https://doi.org/10.1080/19420862.2021.1890411
  64. Mangsbo, S. M., Sandin, L. C., Anger, K., Korman, A. J., Loskog, A. and Totterman, T. H. (2010) Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. J. Immunother. 33, 225-235. https://doi.org/10.1097/cji.0b013e3181c01fcb
  65. Mhawech-Fauceglia, P., Zhang, S., Terracciano, L., Sauter, G., Chadhuri, A., Herrmann, F. R. and Penetrante, R. (2007) Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using mutipletumour tissue microarray technique. Histopathology 50, 472-483. https://doi.org/10.1111/j.1365-2559.2007.02635.x
  66. Miyoshi, Y., Ando, A., Egawa, C., Taguchi, T., Tamaki, Y., Tamaki, H., Sugiyama, H. and Noguchi, S. (2002) High expression of Wilms' tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin. Cancer Res. 8, 1167-1171.
  67. Motzer, R. J., Tannir, N. M., McDermott, D. F., Aren Frontera, O., Melichar, B., Choueiri, T. K., Plimack, E. R., Barthelemy, P., Porta, C., George, S., Powles, T., Donskov, F., Neiman, V., Kollmannsberger, C. K., Salman, P., Gurney, H., Hawkins, R., Ravaud, A., Grimm, M. O., Bracarda, S., Barrios, C. H., Tomita, Y., Castellano, D., Rini, B. I., Chen, A. C., Mekan, S., McHenry, M. B., Wind-Rotolo, M., Doan, J., Sharma, P., Hammers, H. J. and Escudier, B.; CheckMate 214 Investigators (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277-1290. https://doi.org/10.1056/nejmoa1712126
  68. Mullard, A. (2021) FDA approves first BCMA-targeted CAR-T cell therapy. Nat. Rev. Drug Discov. 20, 332.
  69. Nair-Gupta, P., Diem, M., Reeves, D., Wang, W., Schulingkamp, R., Sproesser, K., Mattson, B., Heidrich, B., Mendonca, M., Joseph, J., Sendecki, J., Foulk, B., Chu, G., Fink, D., Jiao, Q., Wu, S. J., Packman, K., Elsayed, Y., Attar, R. and Gaudet, F. (2020) A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia. Blood Adv. 4, 906-919. https://doi.org/10.1182/bloodadvances.2019001188
  70. Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Locke, F. L., Lin, Y., Jain, N., Daver, N., Gulbis, A. M., Adkins, S., Rezvani, K., Hwu, P. and Shpall, E. J. (2018) Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat. Rev. Clin. Oncol. 15, 218. https://doi.org/10.1038/nrclinonc.2018.20
  71. Ott, P. A., Hu, Z., Keskin, D. B., Shukla, S. A., Sun, J., Bozym, D. J., Zhang, W., Luoma, A., Giobbie-Hurder, A., Peter, L., Chen, C., Olive, O., Carter, T. A., Li, S., Lieb, D. J., Eisenhaure, T., Gjini, E., Stevens, J., Lane, W. J., Javeri, I., Nellaiappan, K., Salazar, A. M., Daley, H., Seaman, M., Buchbinder, E. I., Yoon, C. H., Harden, M., Lennon, N., Gabriel, S., Rodig, S. J., Barouch, D. H., Aster, J. C., Getz, G., Wucherpfennig, K., Neuberg, D., Ritz, J., Lander, E. S., Fritsch, E. F., Hacohen, N. and Wu, C. J. (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217-221. https://doi.org/10.1038/nature22991
  72. Palmer, D. C., Guittard, G. C., Franco, Z., Crompton, J. G., Eil, R. L., Patel, S. J., Ji, Y., Van Panhuys, N., Klebanoff, C. A., Sukumar, M., Clever, D., Chichura, A., Roychoudhuri, R., Varma, R., Wang, E., Gattinoni, L., Marincola, F. M., Balagopalan, L., Samelson, L. E. and Restifo, N. P. (2015) Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J. Exp. Med. 212, 2095-2113. https://doi.org/10.1084/jem.20150304
  73. Porter, D. L., Kalos, M., Zheng, Z., Levine, B. and June, C. (2011a) Chimeric antigen receptor therapy for B-cell malignancies. J. Cancer 2, 331-332. https://doi.org/10.7150/jca.2.331
  74. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. and June, C. H. (2011b) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725-733. https://doi.org/10.1056/NEJMoa1103849
  75. Ramachandran, I., Lowther, D. E., Dryer-Minnerly, R., Wang, R., Fayngerts, S., Nunez, D., Betts, G., Bath, N., Tipping, A. J., Melchiori, L., Navenot, J. M., Glod, J., Mackall, C. L., D'Angelo, S. P., Araujo, D. M., Chow, W. A., Demetri, G. D., Druta, M., Van Tine, B. A., Grupp, S. A., Abdul Razak, A. R., Wilky, B., Iyengar, M., Trivedi, T., Winkle, E. V., Chagin, K., Amado, R., Binder, G. K. and Basu, S. (2019) Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J. Immunother. Cancer 7, 276. https://doi.org/10.1186/s40425-019-0762-2
  76. Rapoport, A. P., Stadtmauer, E. A., Binder-Scholl, G. K., Goloubeva, O., Vogl, D. T., Lacey, S. F., Badros, A. Z., Garfall, A., Weiss, B., Finklestein, J., Kulikovskaya, I., Sinha, S. K., Kronsberg, S., Gupta, M., Bond, S., Melchiori, L., Brewer, J. E., Bennett, A. D., Gerry, A. B., Pumphrey, N. J., Williams, D., Tayton-Martin, H. K., Ribeiro, L., Holdich, T., Yanovich, S., Hardy, N., Yared, J., Kerr, N., Philip, S., Westphal, S., Siegel, D. L., Levine, B. L., Jakobsen, B. K., Kalos, M. and June, C. H. (2015) NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914-921. https://doi.org/10.1038/nm.3910
  77. Reck, M., Rodriguez-Abreu, D., Robinson, A. G., Hui, R., Csoszi, T., Fulop, A., Gottfried, M., Peled, N., Tafreshi, A., Cuffe, S., O'Brien, M., Rao, S., Hotta, K., Leiby, M. A., Lubiniecki, G. M., Shentu, Y., Rangwala, R. and Brahmer, J. R.; KEYNOTE-024 Investigators (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823-1833. https://doi.org/10.1056/NEJMoa1606774
  78. Riley, R. S., June, C. H., Langer, R. and Mitchell, M. J. (2019) Delivery technologies for cancer immunotherapy. Nat. Rev. Drug Discov. 18, 175-196. https://doi.org/10.1038/s41573-018-0006-z
  79. Robbins, P. F., Kassim, S. H., Tran, T. L., Crystal, J. S., Morgan, R. A., Feldman, S. A., Yang, J. C., Dudley, M. E., Wunderlich, J. R., Sherry, R. M., Kammula, U. S., Hughes, M. S., Restifo, N. P., Raffeld, M., Lee, C. C., Li, Y. F., El-Gamil, M. and Rosenberg, S. A. (2015) A pilot trial using lymphocytes genetically engineered with an NYESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019-1027. https://doi.org/10.1158/1078-0432.CCR-14-2708
  80. Rosenberg, S. A., Packard, B. S., Aebersold, P. M., Solomon, D., Topalian, S. L., Toy, S. T., Simon, P., Lotze, M. T., Yang, J. C. and Seipp, C. A. (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676-1680. https://doi.org/10.1056/NEJM198812223192527
  81. Rosenberg, S. A., Yang, J. C., Sherry, R. M., Kammula, U. S., Hughes, M. S., Phan, G. Q., Citrin, D. E., Restifo, N. P., Robbins, P. F., Wunderlich, J. R., Morton, K. E., Laurencot, C. M., Steinberg, S. M., White, D. E. and Dudley, M. E. (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using Tcell transfer immunotherapy. Clin. Cancer Res. 17, 4550-4557. https://doi.org/10.1158/1078-0432.ccr-11-0116
  82. Rosenthal, M. A., Balana, C., van Linde, M. E., Sayehli, C., Fiedler, W. M., Wermke, M., Massard, C., Mellinghoff, I. K., Khasraw, M., Ang, A., Rasmussen, E., Kast, J., Stienen, S. and Cloughesy, T. F. (2019) ATIM-49 (LTBK-01). AMG 596, a novel anti-EGFRvIII bispecific T cell engager (BITE(®)) molecule for the treatment of glioblastoma (GBM): planned interim analysis in recurrent GBM (RGBM). Neuro-Oncol. 21, vi283.
  83. Sahin, U., Derhovanessian, E., Miller, M., Kloke, B. P., Simon, P., Lower, M., Bukur, V., Tadmor, A. D., Luxemburger, U., Schrors, B., Omokoko, T., Vormehr, M., Albrecht, C., Paruzynski, A., Kuhn, A. N., Buck, J., Heesch, S., Schreeb, K. H., Muller, F., Ortseifer, I., Vogler, I., Godehardt, E., Attig, S., Rae, R., Breitkreuz, A., Tolliver, C., Suchan, M., Martic, G., Hohberger, A., Sorn, P., Diekmann, J., Ciesla, J., Waksmann, O., Bruck, A. K., Witt, M., Zillgen, M., Rothermel, A., Kasemann, B., Langer, D., Bolte, S., Diken, M., Kreiter, S., Nemecek, R., Gebhardt, C., Grabbe, S., Holler, C., Utikal, J., Huber, C., Loquai, C. and Tureci, O. (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222-226. https://doi.org/10.1038/nature23003
  84. Schadendorf, D., Hodi, F. S., Robert, C., Weber, J. S., Margolin, K., Hamid, O., Patt, D., Chen, T. T., Berman, D. M. and Wolchok, J. D. (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889-1894. https://doi.org/10.1200/JCO.2014.56.2736
  85. Schlothauer, T., Herter, S., Koller, C. F., Grau-Richards, S., Steinhart, V., Spick, C., Kubbies, M., Klein, C., Umana, P. and Mossner, E. (2016) Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng. Des. Sel. 29, 457-466. https://doi.org/10.1093/protein/gzw040
  86. Schultz-Thater, E., Piscuoglio, S., Iezzi, G., Le Magnen, C., Zajac, P., Carafa, V., Terracciano, L., Tornillo, L. and Spagnoli, G. C. (2011) MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies. Int. J. Cancer 129, 1137-1148. https://doi.org/10.1002/ijc.25777
  87. Shimabukuro-Vornhagen, A., Godel, P., Subklewe, M., Stemmler, H. J., Schlosser, H. A., Schlaak, M., Kochanek, M., Boll, B. and von Bergwelt-Baildon, M. S. (2018) Cytokine release syndrome. J. Immunother. Cancer 6, 56. https://doi.org/10.1016/S1278-3218(02)00230-5
  88. Song, S., Han, M., Zhang, H., Wang, Y. and Jiang, H. (2013) Full screening and accurate subtyping of HLA-A*02 alleles through group-specific amplification and mono-allelic sequencing. Cell. Mol. Immunol. 10, 490-496. https://doi.org/10.1038/cmi.2013.33
  89. Stein, A. S., Schiller, G., Benjamin, R., Jia, C., Zhang, A., Zhu, M., Zimmerman, Z. and Topp, M. S. (2019) Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann. Hematol. 98, 159-167. https://doi.org/10.1007/s00277-018-3497-0
  90. Strome, S. E., Dong, H., Tamura, H., Voss, S. G., Flies, D. B., Tamada, K., Salomao, D., Cheville, J., Hirano, F., Lin, W., Kasperbauer, J. L., Ballman, K. V. and Chen, L. (2003) B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 63, 6501-6505.
  91. Sugita, Y., Wada, H., Fujita, S., Nakata, T., Sato, S., Noguchi, Y., Jungbluth, A. A., Yamaguchi, M., Chen, Y. T., Stockert, E., Gnjatic, S., Williamson, B., Scanlan, M. J., Ono, T., Sakita, I., Yasui, M., Miyoshi, Y., Tamaki, Y., Matsuura, N., Noguchi, S., Old, L. J., Nakayama, E. and Monden, M. (2004) NY-ESO-1 expression and immunogenicity in malignant and benign breast tumors. Cancer Res. 64, 2199-2204. https://doi.org/10.1158/0008-5472.CAN-03-3070
  92. Tan, M. P., Gerry, A. B., Brewer, J. E., Melchiori, L., Bridgeman, J. S., Bennett, A. D., Pumphrey, N. J., Jakobsen, B. K., Price, D. A., Ladell, K. and Sewell, A. K. (2015) T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells. Clin. Exp. Immunol. 180, 255-270. https://doi.org/10.1111/cei.12570
  93. Thakur, A., Huang, M. and Lum, L. G. (2018) Bispecific antibody based therapeutics: strengths and challenges. Blood Rev. 32, 339-347. https://doi.org/10.1016/j.blre.2018.02.004
  94. Topp, M. S., Duell, J., Zugmaier, G., Attal, M., Moreau, P., Langer, C., Kronke, J., Facon, T., Salnikov, A. V., Lesley, R., Beutner, K., Kalabus, J., Rasmussen, E., Riemann, K., Minella, A. C., Munzert, G. and Einsele, H. (2020) Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J. Clin. Oncol. 38, 775-783. https://doi.org/10.1200/JCO.19.02657
  95. Turley, S. J., Cremasco, V. and Astarita, J. L. (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669-682. https://doi.org/10.1038/nri3902
  96. Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L., Xu, B., Dada, H., Odorizzi, P. M., Herati, R. S., Mansfield, K. D., Patsch, D., Amaravadi, R. K., Schuchter, L. M., Ishwaran, H., Mick, R., Pryma, D. A., Xu, X., Feldman, M. D., Gangadhar, T. C., Hahn, S. M., Wherry, E. J., Vonderheide, R. H. and Minn, A. J. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373-377. https://doi.org/10.1038/nature14292
  97. Viardot, A., Goebeler, M. E., Hess, G., Neumann, S., Pfreundschuh, M., Adrian, N., Zettl, F., Libicher, M., Sayehli, C., Stieglmaier, J., Zhang, A., Nagorsen, D. and Bargou, R. C. (2016) Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood 127, 1410-1416. https://doi.org/10.1182/blood-2015-06-651380
  98. Wang, T. T. and Ravetch, J. V. (2019) Functional diversification of IgGs through Fc glycosylation. J. Clin. Invest. 129, 3492-3498. https://doi.org/10.1172/jci130029
  99. Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M., Cowey, C. L., Dalle, S., Schenker, M., Chiarion-Sileni, V., Marquez-Rodas, I., Grob, J. J., Butler, M. O., Middleton, M. R., Maio, M., Atkinson, V., Queirolo, P., Gonzalez, R., Kudchadkar, R. R., Smylie, M., Meyer, N., Mortier, L., Atkins, M. B., Long, G. V., Bhatia, S., Lebbe, C., Rutkowski, P., Yokota, K., Yamazaki, N., Kim, T. M., de Pril, V., Sabater, J., Qureshi, A., Larkin, J. and Ascierto, P. A.; CheckMate 238 Collaborators (2017) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824-1835. https://doi.org/10.1056/NEJMoa1709030
  100. Wilkie, S., Burbridge, S. E., Chiapero-Stanke, L., Pereira, A. C., Cleary, S., van der Stegen, S. J., Spicer, J. F., Davies, D. M. and Maher, J. (2010) Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J. Biol. Chem. 285, 25538-25544. https://doi.org/10.1074/jbc.M110.127951
  101. Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T. and Sakaguchi, S. (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271-275. https://doi.org/10.1126/science.1160062
  102. Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J. J., Cowey, C. L., Lao, C. D., Wagstaff, J., Schadendorf, D., Ferrucci, P. F., Smylie, M., Dummer, R., Hill, A., Hogg, D., Haanen, J., Carlino, M. S., Bechter, O., Maio, M., Marquez-Rodas, I., Guidoboni, M., McArthur, G., Lebbe, C., Ascierto, P. A., Long, G. V., Cebon, J., Sosman, J., Postow, M. A., Callahan, M. K., Walker, D., Rollin, L., Bhore, R., Hodi, F. S. and Larkin, J. (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345-1356. https://doi.org/10.1056/nejmoa1709684
  103. Wu, J., Fu, J., Zhang, M. and Liu, D. (2015) Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J. Hematol. Oncol. 8, 104. https://doi.org/10.1186/s13045-015-0195-4
  104. Yang, Y. F., Zou, J. P., Mu, J., Wijesuriya, R., Ono, S., Walunas, T., Bluestone, J., Fujiwara, H. and Hamaoka, T. (1997) Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 57, 4036-4041.
  105. Zacharakis, N., Chinnasamy, H., Black, M., Xu, H., Lu, Y. C., Zheng, Z., Pasetto, A., Langhan, M., Shelton, T., Prickett, T., Gartner, J., Jia, L., Trebska-McGowan, K., Somerville, R. P., Robbins, P. F., Rosenberg, S. A., Goff, S. L. and Feldman, S. A. (2018) Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724-730. https://doi.org/10.1038/s41591-018-0040-8
  106. Zehn, D., Lee, S. Y. and Bevan, M. J. (2009) Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211-214. https://doi.org/10.1038/nature07657
  107. Zhang, Y., Du, X., Liu, M., Tang, F., Zhang, P., Ai, C., Fields, J. K., Sundberg, E. J., Latinovic, O. S., Devenport, M., Zheng, P. and Liu, Y. (2019) Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 29, 609-627. https://doi.org/10.1038/s41422-019-0184-1
  108. Zhao, J., Zhao, J. and Perlman, S. (2012) Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-gamma, IL-2 and IL-2R. PLoS ONE 7, e46241. https://doi.org/10.1371/journal.pone.0046241