Exploring Vaccine Approaches for Immunoprevention in Low-Grade Glioma

Hideho Okada, MD, PhD

Although cancer immunoprevention via oncologic vaccines may not be applicable to all patients following a cancer diagnosis, the approach could provide a benefit for patients with low-grade glioma, according to Hideho Okada, MD, PhD.

Okada, who serves as a professor of neurosurgery, Surgery and Immunology, at the University of California, San Francisco (UCSF), and is a member of the Parker Institute for Cancer Immunotherapy, discussed the utility of vaccine-based approaches for patients with low-grade glioma at The 2024 New York Academy of Sciences Frontiers in Cancer Immunotherapy Symposium.

Low-grade gliomas can harbor IDH mutations, and grade II, III, or IV tumors require a different form of clinical management, Okada said. Although treatment may consist of chemotherapy and radiation, optimal outcomes are achieved in patients who undergo resection and achieve gross total resection; however, not all patients are candidates for this approach.

"Patients who [undergo] gross total resection do relatively [well],” Okada explained in his presentation. “However, if the tumor is in a functional part of the brain, neurosurgeons have to prioritize preservation of function, such as language, motor [skills], and so forth. Therefore, you can't always achieve gross total resection, and surgeons have to stop at partial resection to preserve [these] functions."

In patients who are not eligible for gross total resection, residual tumors could recur. Although patients with low-grade glioma are typically young adults and generally have a strong immune system, allowing them to lead normal lives during the management of their disease, more than 50% experienced malignant transformation to high-grade glioma.

To address this unmet need and potentially lower the rates of patients who experienced malignant transformation, vaccines targeting antigens relevant to high-grade glioma may allow immunoprevention of recurrence.

Development of Vaccine Approaches for Low-Grade Glioma

Data from 2 early phase 1 vaccine studies (NCT00795457; NCT00874861) for patients with WHO grade 2 lower-grade gliomas were published in 2015, and these trials evaluated peptide-based vaccines in combination with poly-ICLC.² Okada reported that patients were treated with vaccinations targeting glioma-associated antigens (GAAs) that are often overexpressed in high-grade glioma but expressed at various levels in low-grade glioma, including IL-13Ra2, EphA2, Survivin, and WT1.

Findings showed that patients with low-grade glioma who had not undergone prior radiotherapy or chemotherapy experienced significantly higher interferon gamma (IFN-γ) responses compared with those who had received prior treatment, as well as compared with both pediatric patients with diffuse midline glioma and adult patients with glioblastoma multiforme who received similar vaccines. However, due to the small and heterogeneous patient populations evaluated in these studies, identifying biomarkers for IFN-γ response was challenging.

"We [then] came up with an idea to preemptively vaccinate [patients with] low-grade gliomas with antigens using allergenic glioblastoma cell lysate to provide glioblastoma-like antigens for those patients,” Okada reported.

This idea led to a neoadjuvant phase 1 trial (NCT02549833) evaluating glioma lysate vaccines in patients with newly diagnosed or recurrent WHO grade II glioma.³ The randomized pilot study was designed to examine this vaccination approach in patients with lower-grade glioma who are clinically indicated for resection surgery. The primary objectives of this investigation were to evaluate the safety and efficacy of the approach in the resected tumor.

In arm 1, 10 patients received GBM6 lysate plus poly-ICLC prior to resection, and in the control arm, 10 patients received no neoadjuvant treatment prior to resection. All patients then went on to receive the vaccine following tumor resection. The vaccine was tolerated, and there was some signal of enhanced responses in patients treated with the neoadjuvant vaccine compared with the control group.

Another randomized phase 1 trial (NCT02549833) evaluated neoadjuvant vaccination with tumor-cell lysate.⁴ The vaccine was well-tolerated and activated CD8-positive T-cell clones, which were detected in the tumor microenvironment. Although there was an upregulation of cytokines and chemokines in the periphery, this was not observed in the central nervous system (CNS) low-grade glioma tissue, contrasting with findings from previous glioblastoma trials, Okada noted. To develop effective immunotherapy for IDH-mutant low-grade glioma, novel strategies must be integrated to enhance the penetration of immune effectors into the tumor tissue, given the intact blood-brain barrier, he continued.

Finally, Okada referenced another phase 1 trial (NCT02924038) that evaluated a combinatory vaccine regimen using IMA950, poly-ICLC, and the anti-CD27 varlilumab in patients with WHO grade 2 low-grade glioma via presurgical vaccine administrations.⁵ It was hypothesized that the regimen would be safe and that varlilumab would enhance the induction of vaccine-reactive T cells. Although the regimen was well-tolerated and induced vaccine-reactive T-cell responses in the peripheral blood, varlilumab did not enhance T-cell response. Additionally, varlilumab promoted the effector memory phenotype of T cells in the peripheral blood; however, tumor-infiltrating leukocytes did not exhibit vaccine-reactive T-cells or the effects of varlilumab.

Impact of IDH Mutations in the Tumor Microenvironment of Low-Grade Glioma

Another investigation found that lower expression levels of CD8-positive T-cell–associated and chemokine genes in IDH-mutated lower-grade glioma patients suppressed STAT1 compared with IDH wild-type disease.⁶

"This discovery highlighted that the IDH mutation downregulates the function of STAT1. [This] results in downregulation of important chemokine genes essential for T-cell infiltration to the CNS tumor, thereby creating an immuno-exclusive environment,” Okada continued. “However, we also found that if you use an inhibitor of IDH-mutant enzyme activity, it can reverse the pathway, and you can recover T-cell expression.”

Research published in the New England Journal of Medicine showing that in the double-blind, phase 3 INDIGO trial (NCT04164901), patients with grade II lower-grade glioma treated with vorasidenib (AG-881), an oral brain penetrant inhibitor of mutant IDH1 and IDH2 enzymes, achieved improved progression-free survival compared with patients treated with placebo.⁷

These findings have informed continued investigation of agents such as vorasidenib, including studies combining them with either mutated or non-mutated peptides and other immunotherapy approaches.¹

Novel Neoantigens for Low-Grade Glioma Treatment

In his presentation, Okada said that cancer-specific alternative splicing events generate targetable neoantigens in gliomas, which are the basis for further research. Investigators have hypothesized that based on the unique epigenetic statuses of low-grade gliomas, such as IDH mutations, glioma-specific alternative splicing events generate targetable immunogenic neoantigens.

Utilizing currently available data, investigators hope to find a target that presents in at least 10% of patients who have the same type of tumor.

“There are some functions that are relatively tumor-wide and also present permanent,” Okada stated. "In the future, immunotherapy may play a role in combination strategy such as IDH inhibitors.”

References

1. Okada H. Vaccine approaches for patients with lower-grade glioma as a step toward cancer immunoprevention. Presented at: Frontiers in Cancer Immunotherapy 2024; May 21-21, 2024; New York, NY.
2. Okada H, Butterfield LH, Hamilton RL, et al. Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC. Clin Cancer Res. 2015;21(2):286-294. doi:10.1158/1078-0432.CCR-14-1790
3. Neo-adjuvant evaluation of glioma lysate vaccines in WHO grade II glioma. UCSF Clinical Trials. Accessed May 22, 2024. https://clinicaltrials.ucsf.edu/trial/NCT02549833
4. Ogino H, Taylor JW, Nejo T, et al. Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas. J Clin Invest. 2022;132(3):e151239. doi:10.1172/JCI151239.
5. Saijo A, Ogino H, Butowski NA, et al. A combinatory vaccine with IMA950 plus varlilumab promotes effector memory T-cell differentiation in the peripheral blood of patients with low-grade gliomas. Neuro Oncol. 2024;26(2):335-347. doi:10.1093/neuonc/noad185.
6. Kohanbash G, Carrera DA, Shrivastav S, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest. 2017;127(4):1425-1437. doi:10.1172/JCI90644.
7. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023;389(7):589-601. doi:10.1056/NEJMoa2304194.