Phase IB Study of Gene-Mediated Cytotoxic Immunotherapy Adjuvant to Up-Front Surgery and Intensive Timing Radiation for Malignant Glioma

Abstract

A B S T R A C T PurposeDespite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O 6 -methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. Patients and MethodsPatients with newly diagnosed malignant glioma received AdV-tk at 3 ϫ 10 10 , 1 ϫ 10 11 , or 3 ϫ 10 11 vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity.Temozolomide was administered after completing valacyclovir treatment. ResultsAccrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3 ϩ T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. ConclusionAdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Coinhibitory Pathways in Immunotherapy for Cancer

“…Local delivery of oncolytic viruses is an alternative strategy to promote immunogenic tumor lysis characterized by antiviral and antitumor immune responses with increased CD8 + T cell infiltration and PD-L1 upregulation (192)(193)(194)(195)(196)(197). Localized intratumoral therapy with an oncolytic Newcastle disease virus in conjunction with systemic CTLA-4 blockade effectively eliminated distant established tumors in a B16 melanoma model (198).…”

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…Extensive necrosis along with a small rim of viable tumor was noted at subsequent autopsy at many of the metastatic sites including the brain lesion [40]. Along the same lines, anecdotal reports highlight the occurrence of pseudoprogression among brain tumor patients treated with a variety of vaccine regimens [38,[41][42][43].…”

Switching a Replication-Defective Adenoviral Vector into a Replication-Competent, Oncolytic Adenovirus

“…For instance, an RD vector could be utilized first to deliver an immunostimulatory gene (in lieu of the GFP transgene in proAd⌬24.GFP) in a tumor, and this immunostimulation could then be amplified by delivery of the Flp vector to generate virusmediated oncolysis. As an example of this approach, we recently published a clinical trial in which human subjects afflicted by malignant glioma were treated with peritumoral injections of an RD adenoviral vector expressing the HSV-tk (thymidine kinase) transgene (23). The transgene product provides chemosensitivity to the prodrug valacyclovir but also is highly immunogenic, leading to an immune response against HSV tk-expressing cancer cells (22).…”