**6. References**


Ultrafractionated Radiation Therapy (3 daily doses of 0.75 Gy) -

*Phys*, 40, 51–55.

1011-1018.

A New and Promising Radiotherapy Schedule for Glioblastoma Patients 411

Scott CB, Scarantino C, Urtasun R, et al. (1998). Validation and predictive power of

Short SC, Mayes CR, Woodcock M, et al. (1999a). Low dose hypersensitivity in the T98G

Short SC, Mitchell SA, Boulton P, et al. (1999b). The response of human glioma cell lines to

Short SC, Kelly J, Mayes CR, et al. (2001). Low-dose hypersensitivity after fractionated low-

Singh, B, Arrand JE, Joiner MC. (1994). Hypersensitive response of normal human lung

Stewart LA. (2002). Chemotherapy in adult high-grade glioma: a systematic review and

Stupp R, Mason WP, van den Bent MJ, et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. *N Engl J Med*, 352, 987-996. Taghian A, Suit H, Pardo F, et al. (1992). In vitro intrinsic radiation sensitivity of

Taghian A, Ramsay J, Allalunis-Turner J, et al. (1993). Intrinsic radiation sensitivity may not

Turesson I, Joiner MC. (1996). Clinical evidence of hypersensitivity to low doses in

Walker MD, Alexander E, Jr, Hunt WE, et al. (1978). Evaluation of BCNU and/ or

Walker MD, Green SB, Byar DP, et al. (1980). Randomized comparisons of radiotherapy and

Van den Bent MJ, Carpentier AF, Brandes AA, et al. (2006). Adjuvant procarbazine,

Watanabe K, Tachibana O, Sata K, et al. (1996). Overexpression of the EGF receptor and *p53* 

Westphal M, Hilt DC, Bortey E, et al. (2003). A phase 3 trial of local chemotherapy with

Wouters BG, Skarsgard LD. (1994). The response of a human tumor cell line to low radiation

doses: evidence of enhanced sensitivity. *Radiat Res*, 138, S76–80.

meta-analysis of individual patient data from 12 randomised trials. *Lancet*; 359,

be the major determinant of the poor clinical outcome of glioblastoma multiforme.

radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. *J* 

nitrosoureas for the treatment of malignant glioma after surgery. *N Engl J Med*, 303,

lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European organisation for research and treatment of cancer phase III

mutations are mutually exclusive in the evolution of primary and secondary

biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary

epithelial cells at low radiation doses. *Int J Radiat Biol*, 65, 457-464.

glioblastoma multiforme. *Int J Radiat Oncol Biol Phys*, 3, 55– 62.

*Int J Radiat Oncol Biol Phys*, 25, 243–249.

radiotherapy. *Radiother Oncol*, 40, 1–3.

*Neurosurg*, 49, 333–343.

trial. *J Clin Oncol*, 24, 2715-2722.

glioblastomas. *Brain Pathol*, 6, 217–223.

malignant glioma. *Neuro-Oncol*, 5, 79-88.

1323–1329

human glioblastoma cell line. *Int J Radiat Biol*, 75, 847–855.

low-dose radiation exposure. *Int J Radiat Biol*, 75, 1341-1348.

dose irradiation in vitro. *Int J Radiat Biol*, 77, 655-664.

Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. *Int J Radiat Oncol Biol* 


Joiner MC, Denekamp J. (1986). The effect of small radiation doses on mouse skin. *British J* 

Joiner MC, Denekamp J, Maughan RL. (1986). The use of 'top-up' experiments to investigate

Joiner MC, Johns H. (1988). Renal damage in the mouse: the response to very small doses

Joiner MC, Marples B, Johns H. (1993a). The response of tissues to very low doses per

Joiner MC, Marples B, Johns H. (1993b). The limitation of the linear–quadratic model at low

Joiner MC, Lambin P, Malaise EP, et al. (1996). Hypersensitivity to very-low single radiation

Joiner MC, Marples B, Lambin P, et al. (2001). Low-dose hypersensitivity: current status and

Kleihues P, Ohgaki H. (1999). Primary and secondary glioblastoms: from concept to clinical

Krause M, Hessel F, Wohlfarth J, et al. (2003). Ultrafractionation in A7 human malignant

Lambin P, Marples B, Fertil B, et al. (1993a). Hypersensitivity of a human tumour cell line to

Lambin P, Malaise EP, Joiner MC. (1993b). Megafractionnement: une methode pour agir sur les tumeurs intrinsequement radioresistantes? *Bull Cancer Radiother*, 80, 417–423. Lambin P, Coco-Martin J, Legal JD, et al. (1994a) Intrinsic radiosensitivity and chromosome

Lambin P, Malaise EP, Joiner MC. (1994b). The effect of very low radiation doses on the human bladder carcinoma cell line RT112. *Radiother Oncol*, 32, 63-72. Lambin P, Fertil B, Malaise EP, et al. (1994c). Multiphasic survival curves for cells of human

Lambin P, Malaise EP, Joiner MC. (1996). Might intrinsic radioresistance of human tumour

McDonald DR, Cascino TL, Schold SC, et al. (1990). Response criteria for phase II studies of

Marples B, Lam GK, Zhou H, et al. (1994). The response of Chinese hamster V79-379A cells

Marples B, Lambin P, Skov KA, et al. (1997). Low dose hyper-radiosensitivity and increased

Pedeux R, Boniol M, Dore JF, et al. (2003). Ultrafractionation radiation therapy of human

cells be induced by radiation? *Int J Radiat Biol*, 69, 279-290.

supratentorial malignant glioma. *J Clin Oncol*, 8, 1277–1280.

dependent on linear energy transfer. *Radiat Res*, 138, S81-4.

gliomas ; a pre-clinical model. *Int J Cancer*, 107, 334.

radioresistance in mammalian cells. *Int J Radiat Biol*, 71, 721-735.

aberration analysis using fluorescence in situ hybridization in cells of two human

tumor cell lines: induced repair or hypersensitive subpopulation? *Radiat Res*, 138,

exposed to negative pi-mesons: evidence that increased radioresistance is

fraction: a reflection of induced repair? *Cancer Res*, 130, 27–40.

possible mechanisms. *Int J Radiat Oncol Biol Phys*, 49, 379-89.

Radiobiology of Tumors (Berlin: Springer), 51–66.

the effect of very small doses per fraction in mouse skin. *Int J Radiat Biol Relat Stud* 

doses per fraction. In H. P. Beck-Bornholdt (ed.), Current Topics in Clinical

doses: its relationship to the adaptive response and induced radioresistance.

*Cancer*, 7, 63–66.

*Phys Chem Med*, 49, 565-580.

*Mutation Res*, 358, 171–183.

diagnosis. *Neuro-Oncol*, 1, 44 –51.

glioma in nude mice. *Int J Cancer*, 79, 377-383.

tumor cell lines. *Radiat Res*, 138, S40–43.

S32–36.

very low radiation doses. *Int J Radiat Biol*, 63, 639-650.

per fraction. *Radiat Res*, 114, 385–398.


**21** 

*Belgium* 

**Immunotherapy for Malignant Gliomas:** 

Since many decades, medical doctors and researchers have been intrigued by the possible beneficial contribution of the immune system in the long-lasting combat against cancer. Both in the cellular and humoral immunity arms, powerful tools are available to target the cancer cell. Moreover, the gradual shift of a focus on aspecific reinforcement of the innate immune system towards a specifically activated adaptive immunity in order to reject cancer cells has dominated the field of the last 10 to 20 years(1). Restorative immunotherapy in which cytokine balances are restored or reset and aspecific adoptive immunotherapy using e.g. natural killer (NK) cells or lymphokine-activated killer (LAK) cells are classical representations of the first wave. Specific adoptive immunotherapy using ex vivo activated antitumor cytotoxic T cells and especially active specific immunotherapy ('cancer vaccines') are representative for the second wave. Thorough changes in the underlying basic immunology mechanism guide these novel approaches. To date, only the different variants of cancer vaccines are able to induce an immunological memory, as such being the only approach potentially protecting the patients for future cancer re-challenges(2). A perceived low rate of classical objective responses, restricted to volume changes of a measurable tumor burden, has been the principal body of criticism

Several new insights however, especially focusing on changes in the micro-environment of the tumors, are only starting to be unraveled. Without any doubt, they're already now revealing much more than the previous tips of the curtains. Nowadays, converging evidence is being gained in a rapid way, for the need to move towards a third wave of immunotherapy approaches, those of the multimodal integrated immunotherapy paradigms, considering all the relevant players in the complex field of tumor

The idea to actively prime cytotoxic T cells to specifically kill a tumor target cell has become a well established scientific fact. Several approaches all aiming to induce specifically activated, tumor-rejecting effector T cells have been investigated and found to be reproducible and reliable technologies. Genetically engineered tumor cells but especially autologous dendritic cells charged with tumor associated antigens have become the most

**2. Proof of the principle: A solid body of preclinical evidence** 

**1. Introduction** 

against these therapies.

immunology.

**A Roadmap for the Future** 

S. De Vleeschouwer and SW. Van Gool

*Catholic University Leuven* 

Wouters BG, Sky AM, Skarsgard LD. (1996). Low dose hypersensitivity and increased radioresistance in a panel of human tumor cell lines with different radiosensitivity. *Radiat Res*, 146, 399–413.
