Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely short time to relapse following standard treatment. Since recurrent GBM is often resistant to subsequent radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative treatment option. Although it is well established that GBM induces immune suppression, it is currently unclear what impact prior conventional therapy has on the ability of GBM cells to modulate the immune environment. In this study, we investigated the interaction between immune cells and glioma cells that had been exposed to chemotherapy or irradiation in vitro. We demonstrate that treated glioma cells are more immunosuppressive than untreated cells and form tumors at a faster rate in vivo in an animal model. Cultured supernatant from in vitro-treated primary human GBM cells were also shown to increase suppression, which was independent of accessory suppressor cells or T regulatory cell generation, and could act directly on CD4 1 and CD8 1 T cell proliferation. While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2. These results reveal for the first time that conventional therapies can alter immunosuppressive pathways in GBM tumor cells, a finding with important implications for the combination of immunotherapy with standard treatment.Despite aggressive upfront therapy for glioblastoma multiforme (GBM), which includes surgical resection, radiotherapy and temozolomide-based chemotherapy, the median time to recurrence is only 6.9 months after standard treatment.1
There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.
Key Points A cellular vaccine incorporating the glycolipid α-galactosylceramide prevents relapse of acute leukemia following cytarabine chemotherapy.
Oral delivery of BCG in a lipid formulation (Liporale™-BCG) targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4+ T cell response, evident by the detection of effector CD4+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.
Vaccine-mediated cancer treatment is unlikely to induce long-term survival unless suppressive mechanisms are overcome. Given the success of antibody-mediated immune checkpoint blockade in relieving regulation of endogenous anti-tumor T cell responses in tumor-burdened hosts, we investigated whether checkpoint blockade could improve the efficacy of responses induced with a whole tumor-cell vaccine. We show that administration of a single dose of blocking antibody was sufficient to significantly enhance antitumor activity of the vaccine, inducing complete radiological regression of established intracranial tumors. The antibody or vaccine alone were ineffective in this setting. The antibody had to be administered before, or close to, vaccine administration, suggesting CTLA-4 blockade had an impact on early priming events. The combined treatment resulted in enhanced trapping of leukocytes in the lymphoid tissues, including T cells that had undergone significant proliferation. There were no obvious changes in the stimulatory function of antigen-presenting cells or the number and function of regulatory T cells, suggesting T cells were the targets of the checkpoint blockade. While tumors regressing under combined treatment were highly infiltrated with a variety of leukocytes, tumor eradication was dependent on CD4 T cells. Analysis of the TCR repertoire showed that the addition of anti-CTLA-4 at priming reshaped the repertoire of tumor infiltrating T cells. In particular, the oligoclonal populations became greater in magnitude and more diverse in specificity. Using anti-CTLA-4 in a restricted way to promote the priming phase of an anti-cancer vaccine may offer a useful way of harnessing clinical benefit from this powerful agent.
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