Main Article Content
Immunotherapy is effective in treating patients with a variety of cancers. We developed and employed an immunotherapeutic protocol that combined intra-tumor injection of autologous immature dendritic cells with standard of care radiation to treat patients with a variety of different advanced solid tumors. To assess patients’ cellular immune response to their tumors,
pre and post treatment peripheral blood mononuclear cells (PBMC) were assayed for their capacity to kill autologous tumor cell lines that had been established from patients with different advanced solid tumors. Peripheral blood lymphocytes obtained post treatment were cytotoxic to autologous but not allogeneic tumor cell lines. Cytotoxic activity increased as relative numbers of CD8+CD56+ dual positive lymphoid cells increased in PBMC obtained post treatment. The autologous tumor cell line directed cytotoxicity was shown to be mediated by both innate and adaptive immune mechanisms. The cytotoxicity of PBMC obtained post treatment was enhanced after co-culture with autologous and not allogeneic tumor cell line lysates.
To assess a humoral immune to an autologous tumor antigen, antibody activity to mesothelin, a tumor associated antigen expressed in a variety of solid tumors, increased in post treatment serum samples from lung cancer patients. Sera containing these antibodies mediated antibody directed cellular cytotoxicity to mesothelin expressing tumor cell lines.
The objective of cancer therapy is to enhance quality of life and increase survival. Survival of 96 patients with a variety different advanced cancer, treated on this protocol over a 3-year period and followed for 1000+ days was significantly increased in patients with low tumor burden (lesion at <5 sites with diameters < 3cm) (Km= <,0.0001) regardless of malignancy. These findings support the application of this combination of immunotherapy and radiation in the treatment of cancer patients with advanced disease.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
2. Yimo S , Fenge L, Heather S, Kyle J , Amjad H Talukder ,et al. Evolution of CD8+ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer. Cells.2021 Sep10; 2379.doi.10.3390/cells10092379
3. Liu QJ, Gao B. Manipulation of MHC-I/TCR interaction for immune therapy.Cell Mol Immunol. 2008 Jun;5(3):171-82. doi: 10.1038/cmi.2008.21.PMID: 1858239
4. Sreya Bagchi, Robert Yuan Edgar G Engleman. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annurevpath - 2021 Jan 24;16:223-249 doi: 10.1146/ 042020-042741. Epub 2020 Nov 16 doi: 10.1146
5. Rotte A Combination of CTLA-4 and PD-1 blockers for treatment of cancer.J Exp Clin Cancer Res. 2019 Jun 13;38(1):255. doi: 10.1186/s13046-019-1259-z.
6. Marple AH, Bonifant CL, Shah NN. Improving CAR T-cells: The next generation. Semin Hematol. 2020;57(3):115-21
7. Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. Int J Mol Sci. 2019 Mar 14;20(6):1283. doi: 10.3390/ijms20061283.PMID
8. Freyer CW, Porter DL.J Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies. Allergy Clin Immunol. 2020 Nov;146(5):940-948. doi: 10.1016/j.jaci.2020.07.025. Epub 2020 Aug 6.PMID: 32771558
9. Reuschenbach M, von Knebel Doeberitz M, Wentzensen N. A systematic review of humoral immune responses against tumor antigens. Cancer Immunol Immunother. 2009;58(10):1535-44.
10. Michels J, Becker N, Suciu S, Kaiser I, Benner A, Kosaloglu-Yalcin Z, et al. Multiplex bead-based measurement of humoral immune responses against tumor-associated antigens in stage II melanoma patients of the EORTC18961 trial. Oncoimmunology. 2018;7(6):e1428157.
11. Voskens CJ, Watanabe R, Rollins S, Campana D, Hasumi K, Mann DL. Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity. J Exp Clin Cancer Res. 2010;29:134
12. Saxena M, Balan S, Roudko V, Bhardwaj N. Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng. 2018;2(6):341-6.
13. Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. Front Immunol. 2018;9:3176.
14. Fu C, Jiang A. Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment.
..Front Immunol. 2018 Dec 20;9:3059. doi: 10.3389/fimmu.2018.03059.
15. Gardner A, Ruffell B. Dendritic Cells and Cancer Immunity. Trends Immunol. 2016;37(12):855-65.
16. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4(3):328-.
17. Hasumi K, Aoki Y, Wantanabe R, Mann DL. Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy. Oncoimmunology. 2013;2(10):e26381.
18. Hasumi K, Aoki Y, Watanabe R, Hankey KG, Mann DL. Therapeutic response in patients with advanced malignancies treated with combined dendritic cell-activated T cell-based immunotherapy and intensity-modulated radiotherapy. Cancers (Basel). 2011;3(2):2223-42.
19. Mann DL, Celluzzi CM, Hankey KG, Harris KM, Watanabe R, Hasumi K. Combining conventional therapies with intratumoral injection of autologous dendritic cells and activated T cells to treat patients with advanced cancers. Ann N Y Acad Sci. 2009;1174:41-50
20. Pita-Lopez ML, Pera A, Solana R. Adaptive Memory of Human NK-like CD8(+) T-Cells to Aging, and Viral and Tumor Antigens. Front Immunol. 2016;7:616.
21. Garofano F, Gonzalez-Carmona MA, Skowasch D, Schmidt-Wolf R, Abramian A, Hauser S, et al. Clinical Trials with Combination of Cytokine-Induced Killer Cells and Dendritic Cells for Cancer Therapy. Int J Mol Sci. 2019;20(17).
22. Zhao Y, Qiao G, Wang X, Song Y, Zhou X, Jiang N, et al. Combination of DC/CIK adoptive T cell immunotherapy with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients: a prospective patients' preference-based study (PPPS). Clin Transl Oncol. 2019;21(6):721-8.
23. Meehan KR, Talebian L, Tosteson TD, Hill JM, Szczepiorkowski Z, Sentman CL, et al. Adoptive cellular therapy using cells enriched for NKG2D+CD3+CD8+T cells after autologous transplantation for myeloma. Biol Blood Marrow Transplant. 2013;19(1):129-3.
24. Aarntzen EH, Bol K, Schreibelt G, Jacobs JF, Lesterhuis WJ, Van Rossum MM, et al. Skin-test infiltrating lymphocytes early predict clinical outcome of dendritic cell-based vaccination in metastatic melanoma. Cancer Res. 2012;72(23):6102-10.
25. Finkelstein SE, Iclozan C, Bui MM, Cotter MJ, Ramakrishnan R, Ahmed J, et al. Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients. International Journal of Radiation Oncology*Biology*Physics. 2012 2012/02/01/;82(2):924-32.
26. Fujiwara S, Wada H, Miyata H, Kawada J, Kawabata R, Nishikawa H, et al. Clinical Trial of the Intrtumaral Administration of Labeled DC Combined With Systemic Chemotherapy for Esophageal Cancer. Journal of Immunotherapy. 2012;35(6).
27. Nikitina EY, Gabrilovich DI. Combination of γ-irradiation and dendritic cell administration induces a potent Anti-tumor response in tumor-bearing mice: Approach to treatment of advanced stage cancer. International Journal of Cancer. 2001 2001/12/15;94(6):825-.
28. Pierce RH, Campbell JS, Pai SI, Brody JD, Kohrt HEK. In-situ tumor vaccination: Bringing the fight to the tumor. Human Vaccines & Immunotherapeutic. 2015 2015/08/03;11(8): 1901-9.
29. Song W, Levy R. Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Naive Dendritic Cells. Cancer Research. 2005;65(13):5958.
30. Tanaka F, Yamaguchi H, Ohta M, Mashino K, Sonoda H, Sadanaga N, et al. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific Anti-tumor effect in vivo. International Journal of Cancer. 2002 2002/09/20;101(3):265-9.
31. Teitz-Tennenbaum S, Li Q, Rynkiewicz S, Ito F, Davis MA, McGinn CJ, et al. Radiotherapy Potentiates the Therapeutic Efficacy of Intratumoral Dendritic Cell Administration. Cancer Research. 2003;63(23):8466.
32. Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer. 2000 2000/12/15;89(12):2646-
33. Hong WX, Haebe S, Lee AS, Westphalen CB, Norton JA, Jiang W, et al. Intratumoral Immunotherapy for Early-stage Solid Tumors. Clin Cancer Res. 2020;26(13):3091-9.
34. Subbiah V, Murthy R, Hong DS, Prins RM, Hosing C, Hendricks K, et al. Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers. Clin Cancer Res. 2018;24(16):3845-56.
35. Borst J, Ahrends T, Babala N, Melief CJM, Kastenmuller W. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635-47.
36. Conejo-Garcia JR, Biswas S, Chaurio R. Humoral immune responses: Unsung heroes of the war on cancer. Semin Immunol. 2020;49:101419.
37. Almagro JC, Daniels-Wells TR, Perez-Tapia SM, Penichet ML. Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy. Front Immunol. 2017;8:1751.
38. Chang K, Pastan I, Willingham MC. Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer. 1992;50(3):373-81
39. Pastan I, Hassan R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 2014;74(11):2907-12.
40. De Fonseka D, Arnold DT, Stadon L, Morley A, Keenan E, Darby M, et al. A prospective study to investigate the role of serial serum mesothelin in monitoring mesothelioma. BMC Cancer. 2018 2018/02/17;18(1):199.
41. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. European Journal of Cancer. 2008 2008/01/01/;44(1):46-53.
42. Morello A, Sadelain M, Adusumilli PS. Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discov. 2016;6(2):133-46. BMC Cancer. 2018 2018/02/17;18(1):199.
43. Zhao X, Subramanyam B, Sarapa N, Golfier S, Dinter H. Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors. Clinical cancer drugs. 2016;3(2).Zhang X, Shen W, 44. 44.
44. Dong X, Fan J, Liu L, Gao X, et al. Identification of novel autoantibodies for detection of malignant mesothelioma. PloS one. 2013;8(8).
45. Beatty GL, O'Hara MH, Lacey SF, Torigian DA, Nazimuddin F, Chen F, et.al. Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells AgainsPancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology. 2018 Jul;155(1):29-32. doi: 10.1053/j.gastro.2018.03.029. Epub 2018 Mar 20. PMID: 29567081.