Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2

Abstract

For a single-dose toxicity assessment, five patients with recurrent malignant glioma (ages 29-46 years) were treated with intracavitary alloreactive cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2). The trial tested the hypothesis that alloreactive CTL, sensitized to the major histocompatibility complex (MHC) proteins of the patient, offer selective, targeted killing of glioma cells that express MHC. Patient lymphocytes, which also express MHC, were irradiated and placed into CellMax artificial capillary systems with lymphocytes from MHC-disparate donors and CTL developed over a 2- to 3-week period with a low concentration of IL-2. The CTL largely expressed CD3 and CD11a/CD8 markers and lysed targets displaying patient MHC. CTL were implanted into the tumor bed at surgery and a catheter was used for subsequent infusions. Patients received one to five treatment cycles every other month; one cycle generally consisted of two or three CTL infusates administered within a 1- to 2-week period. Different unrelated donors were used for each cycle. Treatment was well tolerated; transient toxicity at grades 1-3 was recorded by NCI Common Toxicity Scale criteria. Two glioblastoma patients have died; one from tumor recurrence locally and the other from recurrence at a site distant from the treatment. Two of the five patients completed five cycles; one anaplastic oligodendroglioma patient shows no evidence of tumor 30 months from the start of immune therapy and an anaplastic astrocytoma patient shows stable disease 28 months after initiation of therapy. One anaplastic oligodendroglioma patient, who dropped the protocol during her second treatment cycle, has no evidence of tumor 28 months after recurrence.

Inmunoterapia en astrocitomas de alto grado: principios y estado actual

“…Para evitar esta complicación, se han desarrollado diferentes vías de administración 50,91 . En los últimos años se ha propuesto como alternativa la utilización de células programadas genéticamente, para producir la liberación prolongada y mantenida de las sustancias deseadas mediante la transducción de genes de citoquinas 58,107 .…”

“…Se han desarrollado otras vías de administración y se utiliza en múltiples protocolos, tanto como terapia única como en combinación con quimioterapia 91 , o terapias celulares 50 . Más recientemente, se ha publicado el desarrollo de biopolímeros de liberación controlada de esta citoquina 83 , y el desarrollo de células modificadas genéticamente para producirla de manera continuada y prolongada 29 .…”

“…Se han realizado múltiples estudios tanto in vitro como in vivo 2,32,50,66,67 , no habiéndose obtenido resultados significativos salvo en casos aislados 32 . Este escaso éxito de la inmunoterapia adoptiva tradicional puede explicarse por múltiples motivos, como son el estado de inmunosupresión de los linfocitos del paciente, los tratamientos corticoideos asociados y su efecto linfosupresor, o la habilidad tumoral para difuminar la acción antitumoral de los linfocitos activados 50 . Con objeto de mejorar la respuesta linfocitaria y, con ello, aumentar la eficacia tumoricida de los linfocitos, se han investigado diferentes estrategias experimentales.…”

Current Immunotherapeutic Strategies for Central Nervous System Tumors

“…IL-2 has also been used in clinical studies with cytotoxic T lymphocytes [43]. Initially, five patients with recurrent glioma were treated with intracavitary CTLs and IL-2.…”

“…Control patients had a median survival of 13.6 months from their initial diagnosis, with a 2-year survival rate of 20%; for the 31 patients who underwent LAK cell placement during the course of their disease, median survival was 17.5 months and the 2-year survival rate was 31% (p2 = 0.012). However, other studies using LAK cells could not reproduce these encouraging outcomes, and one study reported considerable toxicity [42].IL-2 has also been used in clinical studies with cytotoxic T lymphocytes [43]. Initially, five patients with recurrent glioma were treated with intracavitary CTLs and IL-2.…”