Weekly Digests
‹ Back to January

Vaccine and anti-CTLA-4 team up against glioma

January 17, 2018

Surgery, a common treatment option for high-grade glioma, is mostly ineffective long term, however, the resected tumor could serve as a source of antigens for the development of personalized vaccines that could improve long-term outcomes. Field et al. had previously created a vaccine comprised of irradiated glioma cells pulsed with the glycolipid α-galactoceramide (α-GalCer) and tested it in a glioma mouse model. α-GalCer is presented by antigen-presenting cells to natural killer T (NKT) cells via an MHC-I-like molecule CD1d. As CD1d is non-polymorphic and the T cell receptor of NKT cells is mostly invariant, α-GalCer is an attractive immune adjuvant with broad applicability. Although the vaccine prevented tumor development when administered prophylactically, it did not result in long-term survival benefit in a therapeutic setting unless Treg suppression was also addressed. In the current paper, published in OncoImmunology, Field et al. explored adding anti-CTLA-4 just before or close to vaccine administration in an orthotopic mouse model of glioma to target the T cell priming phase and enhance the antitumor response initiated by the vaccine.

In the prophylactic setting, the α-GalCer-pulsed, irradiated GL261 glioma cell vaccine, intravenously injected seven days before subcutaneous GL261 tumor challenge, resulted in significant protection against tumor development. However, when the vaccine was administered therapeutically seven days after tumor challenge, the tumor was not eradicated.

To test whether the addition of immune checkpoint blockade would improve the outcome in the therapeutic setting, the team administered a single dose of anti-CTLA-4 either one day before vaccination or three days after. In both cases, the tumors initially grew, but then completely regressed. Tumor growth was lower when anti-CTLA-4 was administered prior to vaccination.

Moving on to the intracranial tumor setting, neither the vaccine nor anti-CTLA-4 alone had any positive effect on survival, but a single dose of anti-CTLA-4 before vaccination resulted in a significant antitumor response, prevented the onset of tumor-related symptoms in most mice, and significantly prolonged symptom-free survival, with long-term survival averaging 80%. Administering anti-CTLA-4 3 or 7 days after vaccination was significantly less effective, implying that checkpoint blockade was most helpful during immune priming. Mice with complete response rejected subcutaneous tumor challenge 100 days after initial intracranial tumor establishment, indicating the presence of immunological memory. Tumor regression and increased immune cell infiltration into the tumor following combination treatment were confirmed radiologically and histopathologically.

To identify the cellular players involved, the researchers took a closer look at the immune infiltrates in the spleens, lymph nodes, and brains of tumor-bearing mice. Within the spleen and lymph nodes, early timing of CTLA-4 blockade significantly enhanced proliferation of CD4+ and CD8+ T cells (but not Tregs), with the greatest increase observed with combination treatment. CD4+ T cells expanded more than CD8+ T cells, and tumor-specific cells were highly prevalent in the immune infiltrate. In the brain, statistically significant increases in the number of immune cells were only observed with combination treatment, with the majority of the infiltrate consisting of macrophages, microglia, and lymphocytes. Within the T cell compartment, CD4+ T cells were highly represented, while the numbers of CD8+ T cells and Tregs did not change significantly. Examination of the TCR repertoire in the brain revealed that the combination treatment resulted in increased infiltration of diverse oligoclonal T cell populations, although the antigen-specificity of these clones was not determined. Overall, the team discovered that the therapeutic effect of vaccine and anti-CTLA-4 combination treatment was dependent on CD4+ T cells and activated NKT cells. How CD4+ T cells mediate tumor cell elimination in this setting is yet to be determined.

Field et al. demonstrate that early, but not late, administration of anti-CTLA-4 close to immune priming with an α-GalCer-pulsed whole cell vaccine confers long-term survival benefit and tumor regression in an orthotopic glioma mouse model. The researchers hypothesize that using anti-CTLA-4 in this temporally restricted manner rather than the extended multi-dose schedule currently utilized in the clinic, may also avoid the autoimmune side effects commonly observed with this immune checkpoint blockade.

by Anna Scherer

References:

Field C.S., Hunn M.K., Ferguson P.M., Ruedl C., Ancelet L.R., Hermans I.F. Blocking CTLA-4 while priming with a whole cell vaccine reshapes the oligoclonal T cell infiltrate and eradicates tumors in an orthotopic glioma model. Oncoimmunology. 2017 Sep 27

In the Spotlight...

The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients

Matson et al. analyzed stool samples from metastatic melanoma patients prior to anti-PD-1 treatment and found that the species composition of the commensal microbiota was significantly associated with clinical efficacy, with the ratio of beneficial to non-beneficial bacteria being a strong predictor of response. Germ-free mice reconstituted with human fecal matter from responders or non-responders led to the correspondingly enhanced or diminished tumor control, T cell response, and efficacy with anti-PD-L1 therapy in 2 of 3 mice in each group.

Antigen-specific antitumor responses induced by OX40 agonist are enhanced by IDO inhibitor indoximod

Berrong et al. tested the addition of the IDO inhibitor indoximod to a combination of E7 peptide vaccine and OX40 agonist in the murine TC-1 model and found that it slowed tumor growth and increased the rate of complete tumor regression from 20% to 60%. The researchers observed a decrease in IDO activity, as well as increases in the numbers of tumor-infiltrating E7 antigen-specific CD8+ T cells and cytotoxic CD8+GrzB+ T cells.

Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice

Gillissen et al. searched the B cell repertoire of a patient who had experienced a durable graft-versus-AML response following HSCT treatment and identified an antibody, AT1413, which specifically recognized a unique sialylated epitope of CD43 overexpressed in AML, and demonstrated presence of this epitope on all 61 patient-derived leukemic blasts (representing all WHO classifications of AML) that were tested. AT1413 showed antitumor cytotoxicity in vitro and in vivo while sparing non-malignant cells, supporting consideration for clinical evaluation.

Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models

In a comprehensive study with several mouse tumor models (EMT-6, s.c and i.v. B16-F10, MC38, and CT26), Lewis et al. explored the addition of IL-21 to either anti-PD-1 or anti-CTLA-4. IL-21 enhanced the antitumor efficacy of anti-CTLA-4 in four models, and of anti-PD-1 in two models (MC38 and B16-F10). Both combinations reduced the number of surface lung metastases in the i.v. model. Phenotypic analysis of TILs indicated that IL-21 decreased intratumoral Tregs, enhanced CD8+ effector response, and reduced T cell exhaustion.

Phase I study of glypican-3-derived peptide vaccine therapy for patients with refractory pediatric solid tumors

In this phase I clinical trial of GPC3-peptide vaccination against pediatric GPC3-expressing solid tumors, treatment was well-tolerated in all eighteen enrolled patients. Disease control was observed in about two thirds of patients over almost 5 years of evaluation. The vaccine induced GPC3-specific cytotoxic T lymphocyte responses in seven patients (almost all of whom were in remission with diagnosed hepatoblastoma), which correlated with high progression-free and overall survival. Antigen-specific T cells were found in the tumor of the one patient evaluated.

Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer

Using a clinically relevant hepatocellular carcinoma (HCC) model, Liu et al. interrogated the mechanism underlying the antitumor efficacy of sunitinib, an FDA-approved tyrosine-kinase inhibitor, and found that it decreases the frequency of tumor Tregs and subdues their tumor-enhanced immunosuppressive functions (particularly secretion of TGFβ and IL-10), leading to partial recovery of tumor antigen-specific (TAS) CD8+ T cell activity. Combining sunitinib with TAS immunization and adoptive transfer of TAS CD8+ T cells led to complete elimination of established tumors.

A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer

Martin et al. utilized a “mini-line” method of screening CD8+ T cells from a patient with high-grade serous ovarian cancer to identify neoantigen-specific T cells from small volumes of peripheral blood collected prior to clinical relapse. Screening against all 37 mutations for this tumor revealed T cells reactive against 5 neoantigens, one of which produced three independent T cell clones that recognized the tumor. This supports the possibility of generating adoptive cell transfer therapy for preemptive treatment prior to relapse.

Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

Efremova et al. used the MC38 (hypermutated, immunogenic) and CT26 (less mutated, less immunogenic) tumor models to quantitatively evaluate the cancer immunoediting hypothesis and the role of checkpoint blockade in immunoediting. They observed that normal tumor progression is dominated by neutral evolution, in which mutations accumulate independently of their impact on progression or immunogenicity. Checkpoint blockade induces selective pressure by the immune system, which leads to more pronounced immunoediting and results in more homogenous tumors.

Everything New this Week In...