Strong T‑cell costimulation can reactivate tumor antigen‑specific T cells in late‑stage metastasized colorectal carcinoma patients: Results from a phase Ⅰ clinical study

Schirrmacher,Volker; Schlude,Christoph; Weitz,Jürgen; Beckhove,Philipp

doi:10.3892/ijo.2014.2692

Strong T‑cell costimulation can reactivate tumor antigen‑specific T cells in late‑stage metastasized colorectal carcinoma patients: Results from a phase Ⅰ clinical study

Authors:
- Volker Schirrmacher
- Christoph Schlude
- Jürgen Weitz
- Philipp Beckhove
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Affiliations: German Cancer Research Center, Division of Translational Immunology; Department of Surgical Oncology, Heidelberg University Hospital, Heidelberg, Germany
Published online on: October 6, 2014 https://doi.org/10.3892/ijo.2014.2692
Pages: 71-77

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Abstract

T‑cell costimulation is necessary to induce a response of naïve T cells. Whether T‑cell costimulation can also cause reactivation of unreactive, possibly anergized memory T cells (MTCs) from late‑stage cancer patients is unknown. To investigate this question, we developed a bispecific anti‑CD28 fusion protein (bsHN‑CD28) which can easily be attached to the vaccine ATV‑NDV. This virus‑modified autologous tumor cell vaccine has already shown effectivity in colon cancer patients following resection of liver metastases. In this phase Ⅰ clinical study, 14 colorectal carcinoma (CRC) patients with late‑stage disease which could not be operated anymore with curative intent were treated with the vaccine ATV‑NDV to which bsHN‑CD28 was attached. No severe adverse events were recorded. All patients showed an immunological response of tumor‑reactive T cells, at least once during the course of five vaccinations. Also, we demonstrate a dose‑response relationship with the costimulatory molecule added to the vaccine. A partial response of metastases was documented in four patients. The study suggests that the three‑component vaccine is safe and can reactivate possibly anergized T cells from a chronic disease like advanced‑stage cancer.

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1	Fong Y, Fortner J, Sun RL, Brennan MF and Blumgart LH: Clinical score for predicting recurrence after hepatic resection of metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 230:309–318. 1999. View Article : Google Scholar : PubMed/NCBI
2	Galon J, Costes A, Sanchez-Cabo F, et al: Type, density, and location of immune cells within colorectal tumors predict clinical outcome. Science. 313:1960–1964. 2006. View Article : Google Scholar : PubMed/NCBI
3	Ockert D, Schirrmacher V, Beck N, et al: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res. 2:21–28. 1996.
4	Schirrmacher V, Fournier P and Schlag P: Autologous tumor cell vaccines for post-operative active-specific immunotherapy of colorectal carcinoma: long-term patient survival and mechanism of function. Exp Rev Vaccines. 13:117–130. 2014. View Article : Google Scholar : PubMed/NCBI
5	Schulze T, Kemmner W, Weitz J, et al: Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother. 58:61–69. 2009. View Article : Google Scholar
6	Rosenberg SA, Yang JC and Restifo NP: Cancer immunotherapy: moving beyond current vaccines. Nat Med. 10:909–915. 2004. View Article : Google Scholar : PubMed/NCBI
7	Schwartz RH: T cell anergy. Annu Rev Immunol. 21:305–334. 2003. View Article : Google Scholar
8	Greenfield EA, Nguyen KA and Kuchroo VK: CD28/B7 costimulation: a review. Crit Rev Immunol. 18:389–418. 1998. View Article : Google Scholar : PubMed/NCBI
9	Fournier P and Schirrmacher V: Bispecific antibodies and trispecific immunocytokines for targeting the immune system against cancer: preparing for the future. BioDrugs. 27:35–53. 2013. View Article : Google Scholar : PubMed/NCBI
10	Aigner M, Janke M, Lulei M, Beckhove P, Fournier P and Schirrmacher V: An effective tumor vaccine optimized for costimulation via bispecific and trispecific fusion proteins. Int J Oncol. 32:777–789. 2008.PubMed/NCBI
11	Haas C, Lulei M, Fournier P, Arnold A and Schirrmacher V: T-cell triggering by CD3- and CD28-binding molecules linked to a human virus-modified tumor cell vaccine. Vaccine. 23:2439–2453. 2005. View Article : Google Scholar : PubMed/NCBI
12	Haas C, Lulei M, Fournier P, Arnold A and Schirrmacher V: A tumor vaccine containing anti-CD3 and anti-CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes. Int J Cancer. 118:658–667. 2006. View Article : Google Scholar : PubMed/NCBI
13	Koch M, Beckhove P, Op den Winkel J, et al: Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ. Ann Surg. 244:986–992. 2006. View Article : Google Scholar : PubMed/NCBI
14	Sommerfeldt N, Schütz F, Sohn C, Förster J, Schirrmacher V and Beckhove P: The shaping of a polyvalent and highly individual T-cell repertoire in the bone-marrow of breast cancer patients. Cancer Res. 66:8258–8265. 2006. View Article : Google Scholar : PubMed/NCBI
15	Termeer CC, Schirrmacher V, Bröcker EB and Becker JC: Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells. Cancer Gene Ther. 7:316–323. 2000. View Article : Google Scholar : PubMed/NCBI
16	Bai L, Koopmann J, Fiola C, Fournier P and Schirrmacher V: Dendritic cells pulsed with viral oncolysates potently stimulate autologous T cells from cancer patients. Int J Oncol. 21:685–694. 2002.PubMed/NCBI
17	Brischwein K, Schlereth B, Guller B, et al: MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol Immunol. 43:1129–1143. 2006. View Article : Google Scholar : PubMed/NCBI
18	Biburger M, Weth R and Wels WS: A novel bispecific tetravalent antibody fusion protein to target costimulatory activity for T-cell activation to tumor cells overexpressing ErbB2/HER2. J Mol Biol. 346:1299–1311. 2005. View Article : Google Scholar : PubMed/NCBI
19	Müller D, Frey K and Kontermann RE: A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother. 31:714–722. 2008.PubMed/NCBI
20	Schirrmacher V, Haas C, Bonifer R, Ahlert T, Gerhards R and Ertel C: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther. 6:63–73. 1999. View Article : Google Scholar
21	Fournier P, Wilden H and Schirrmacher V: Importance of retinoic acid-inducible gene I and of receptor for Type I interferon for cellular resistance to infection by Newcastle disease virus. Int J Oncol. 40:287–298. 2012.PubMed/NCBI
22	Washburn B and Schirrmacher V: Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. Int J Oncol. 21:85–93. 2002.
23	Grakoui A, Bromley SK, Sumen C, et al: The immunological synapse: a molecular machine controlling T cell activation. Science. 285:221–227. 1999. View Article : Google Scholar : PubMed/NCBI
24	Zitvogel L, Tesniere A and Kroemer G: Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 6:715–727. 2006. View Article : Google Scholar : PubMed/NCBI
25	St Clair EW: The calm after the cytokine storm: lessons from the TGN1412 trial. J Clin Invest. 118:1344–1347. 2008.PubMed/NCBI
26	Feuerer M, Beckhove P, Bai L, Solomayer EF, Bastert G, Diehl IJ, Pedain C, Oberniedermayr M, Schirrmacher V and Umansky V: Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med. 7:452–458. 2001. View Article : Google Scholar : PubMed/NCBI
27	Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hämmerling GJ, Kyewsky B, Hamann A, Umansly V and Schirrmacher V: Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med. 9:1151–1157. 2003. View Article : Google Scholar : PubMed/NCBI
28	Schirrmacher V, Feuerer M, Fournier P, Ahlert T, Umansky V and Beckhove P: T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends Mol Med. 9:526–534. 2003. View Article : Google Scholar : PubMed/NCBI