Pilot Immunotherapy Trial for Recurrent Malignant Gliomas

Summary

This human Phase I trial involves taking the patient's own tumor cells during surgical craniotomy, treating them with an investigational new drug (an antisense molecule) designed to shut down a targeted surface receptor protein, and re-implanting the cells, now encapsulated in small diffusion chambers the size of a dime in the patient's abdomen within 24 hours after the surgery. Loss of the surface receptor causes the tumor cells to die in a process called apoptosis. As the tumor cells die, they release small particles called exosomes, each full of tumor antigens. It is believed that these exosomes as well as the presence of the antisense molecule work together to activate the immune system against the tumor as they slowly diffuse out of the chamber. This combination product therefore serves as a slow-release antigen depot. Immune cells are immediately available for activation outside of the chamber because a wound was created to implant these tumor cells and a foreign body (the chamber) is present in the wound. The wound and the chamber fortify the initial immune response which eventually leads to the activation of immune system T cells that attack and eliminate the tumor. By training the immune system to recognize the tumor, the patient is also protected through immune surveillance from later tumor growth should the tumor recur. Compared to the other immunotherapy strategies, this treatment marshalls the native immune system (specifically the antigen presenting cells, or dendritic cells) rather than engineering the differentiation of these immune cells and re-injecting them. Compared to traditional treatment alternatives for tumor recurrence, including a boost of further radiation and more chemotherapy, this treatment represents potentially greater benefit with fewer risks. This combination product serves as a therapeutic vaccine with an acceptable safety profile, which activates an anti-tumor adaptive immune response resulting in radiographic tumor regression.

Timeline

Start

2012-02-09

Primary completion

2013-06-25

Completion

2013-06-25

Publications

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• Background Brandes AA, Scelzi E, Salmistraro G, Ermani M, Carollo C, Berti F, Zampieri P, Baiocchi C, Fiorentino MV. Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer. 1997 Sep;33(10):1592-6. doi: 10.1016/s0959-8049(97)00167-6.
• Background Cage TA, Lamborn KR, Ware ML, Frankfurt A, Chakalian L, Berger MS, McDermott MW. Adjuvant enoxaparin therapy may decrease the incidence of postoperative thrombotic events though does not increase the incidence of postoperative intracranial hemorrhage in patients with meningiomas. J Neurooncol. 2009 May;93(1):151-6. doi: 10.1007/s11060-009-9886-4. Epub 2009 May 9.
• Background Carpentier A, Laigle-Donadey F, Zohar S, Capelle L, Behin A, Tibi A, Martin-Duverneuil N, Sanson M, Lacomblez L, Taillibert S, Puybasset L, Van Effenterre R, Delattre JY, Carpentier AF. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol. 2006 Jan;8(1):60-6. doi: 10.1215/S1522851705000475.
• Background Chaput N, Schartz NE, Andre F, Taieb J, Novault S, Bonnaventure P, Aubert N, Bernard J, Lemonnier F, Merad M, Adema G, Adams M, Ferrantini M, Carpentier AF, Escudier B, Tursz T, Angevin E, Zitvogel L. Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. J Immunol. 2004 Feb 15;172(4):2137-46. doi: 10.4049/jimmunol.172.4.2137.
• Background Cosaceanu D, Carapancea M, Alexandru O, Budiu R, Martinsson HS, Starborg M, Vrabete M, Kanter L, Lewensohn R, Dricu A. Comparison of three approaches for inhibiting insulin-like growth factor I receptor and their effects on NSCLC cell lines in vitro. Growth Factors. 2007 Feb;25(1):1-8. doi: 10.1080/08977190600702865.
• Background Cunningham CC, Holmlund JT, Schiller JH, Geary RS, Kwoh TJ, Dorr A, Nemunaitis J. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res. 2000 May;6(5):1626-31.
• Background Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001 Aug 2;345(5):340-50. doi: 10.1056/NEJM200108023450506. No abstract available.
• Background Tang J, Flomenberg P, Harshyne L, Kenyon L, Andrews DW. Glioblastoma patients exhibit circulating tumor-specific CD8+ T cells. Clin Cancer Res. 2005 Jul 15;11(14):5292-9. doi: 10.1158/1078-0432.CCR-05-0545.
• Background Tetri S, Hakala J, Juvela S, Saloheimo P, Pyhtinen J, Rusanen H, Savolainen ER, Hillbom M. Safety of low-dose subcutaneous enoxaparin for the prevention of venous thromboembolism after primary intracerebral haemorrhage. Thromb Res. 2008;123(2):206-12. doi: 10.1016/j.thromres.2008.01.018. Epub 2008 Apr 16.
• Background Zimmerman RA. Imaging of adult central nervous system primary malignant gliomas. Staging and follow-up. Cancer. 1991 Feb 15;67(4 Suppl):1278-83. doi: 10.1002/1097-0142(19910215)67:4+3.0.co;2-u.
• Background Dorn A, Kippenberger S. Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators. Curr Opin Mol Ther. 2008 Feb;10(1):10-20.

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