PD-1 blockade enhances the vaccination-induced immune response in glioma

Abstract

DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor– bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

“…Studies were excluded because of following reasons: (1) not sufficient survival data reported, (2) letters, reviews, commentary, perspectives, case reports, conference abstracts, editorials or expert opinion, (3) studies reporting xenograft results in immunodeficient or humanized mice. Overall these search criteria helped short-list 15 research articles 12,15,16,[50][51][52][53][54][55][56][57][58][59][60][61] mentioned in Box S1.…”

Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?

“…Considering anti-PD-L1 antibodies (such as durvalumab currently being tested in patients with GBM, see below), they will certainly need to access the tumor to reach PD-L1-expressing tumor cells, but an effect of anti-PD-L1 on circulating myeloid cells cannot be excluded. Studies in glioma mouse models have demonstrated the efficacy of anti-CTLA4 and anti-PD1 antibodies (161, 162) and studies demonstrating efficacy of anti-PD-L1 antibodies confirmed interest of these targets but do not provide the formal proof than these antibodies are able to enter the brain (144, 163). Brain metastases from melanoma patients can be controlled by ICB antibodies, but with lower efficacy than metastases in extracerebral sites (164).…”

“…At the moment, only one trial combining ICB antibodies with another immunotherapy is ongoing, using autologous DCs pulsed with pp65 CMV mRNA (NCT02529072). As mentioned above, elicitation of antitumor immune responses that reach the tumor is associated with adaptive immune resistance as tumor infiltration by IFN-γ-secreting cells lead to upregulation to PD-L1 in the tumor environment (37), a phenomenon that could be counteracted in a glioma mouse model of tumor-loaded DC vaccination by the concomitant use of anti-PD1 antibodies (162). Therefore, combining DC and other vaccines with ICB antibodies certainly merits further exploration.…”

Prospect of Immunotherapy for Glioblastoma: Tumor Vaccine, Immune Checkpoint Inhibitors and Combination Therapy

“…66) Although no clinical case of HGG treated with immune checkpoint inhibitors combined with vaccine has been reported clinically, PD-1 antibody combined with radiotherapy produce long-term survival in a murine glioma model. 67,68) Combination therapy of a double immune checkpoint blockade also prolonged survival of mice with brain tumors. 69) Clinically, we need to pay attention to serious immune-related adverse events (AEs) after treatment with each immune checkpoint inhibitor, 70,71) and increasing of AEs in combination of immune checkpoint inhibitors.…”