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Table 2 Combinations of immunotherapy and chemotherapy in preclinical GBM models

From: Immunotherapy for glioblastoma: the promise of combination strategies

Combination treatment Protocol Cell line and model Outcome Reference
• Tumor implantation: 2 × 105 cells
• TMZ: 30 mg/kg, 5 consecutive days starting at d8, IP
• anti-PD-1: 10 mg/kg 2x on d13 and d15, IV
• Combined therapy showed better antitumor efficacy than monotherapies with 100% tumor regression
• TMZ abrogated the favorable immunological effects of anti-PD-1 (increased TIL numbers, decreased Treg and exhausted T cell frequencies, increased immunological memory)
Park J., et al. (2018) [123]
TMZ (standard or metronomic dose)
• Tumor implantation: /
• TMZ:
 - Standard dose (SD): 50 mg/kg for 5 consecutive days, IP
 - Metronomic dose (MD): 25 mg/kg for 10 consecutive days, IP
• anti-PD-1: 10 mg/kg 4x every 5 days, IP
• SD TMZ increased exhaustion markers on T cells, while MD TMZ did not lead to T cell exhaustion
• anti-PD-1 reversed the exhaustion induced by SD TMZ in peripheral T cells but not in TILs
• The survival benefit of anti-PD-1 therapy was abrogated by SD TMZ but not by MD TMZ
Karachi A., et al. (2019) [124]
TMZ (low dose)
• Tumor implantation: 5 × 104 cells, right cerebral cortex
• TMZ: 50 μg/kg, 5 consecutive days, IP
• anti-PD-1: 200 μg 3x, IP
• Combined therapy synergistically inhibited GBM tumor growth with a higher median survival time, a reduced tumor volume and 40% long-term survivors
• Combined therapy increased CD4 and CD8 T cell infiltration in tumor lesions
Dai B., et al. (2018) [126]
TMZ or carmustine (BCNU) (systemic or local administration)
• Tumor implantation: 1.3 × 105 cells, left striatum
• Systemic chemotherapy (SC):
 - TMZ: 66 mg/kg, daily from d10 to d14, IP
 - BCNU: 5, 15 and 30 mg/kg, 3x/week for 2 weeks starting at d14, IP
• Local chemotherapy (LC):
 - TMZ: implanted at d10
 - BCNU: implanted at d14
 Polymer impregnated with chemotherapy (wafer), allowing constant release in the TME for at least 2 weeks, placed directly on top of the tumor
• anti-PD-1: 200 μg 3x, on d0, d12, and d14, IP
• Combination of LC and anti-PD-1 induced a robust immune response and survival benefit, with higher numbers of TILs and IFN-γ-secreting CD8 T cells in the brain, a higher Teff/Treg ratio and a higher tumor-infiltrating DC %
• LC preserved the memory response upon rechallenge; SC abrogated it
• SC abrogated the immunological benefits of anti-PD-1, did not provide survival benefit and resulted in severe lymphodepletion and severe depletion of TILs
• SC alone or in combination with anti-PD-1 delayed tumor progression, but tumors recurred
Mathios D., et al. (2016) [125]
TMZ (systemic)
ICD-based DC vaccine
• Tumor implantation: 5 × 105 cells
• ICD-based DC vaccine: 1 × 106 DCs, IP
 - On d2, d9 and d15 – vaccine alone
 - On d21, d28 and d35 – combination
 Production: cancer cells were incubated with hypericin followed by light irradiation, and then, Hyp-PDT-treated cells were mixed with DCs
• TMZ: 40 mg/kg, 6x on d5, d7, d9, d12, d14, and d16
• Combined therapy provided a strong survival benefit with improved median survival and 50% long-term survivors
• The ICD-based vaccine partially overcame the immune-ablating effects of chemotherapy. TMZ decreased the levels of brain-infiltrating CD8 T cells, but the combination decreased the levels of Tregs in the brain
Garg AD., et al. (2016) [127]
TMZ (systemic or local)
GL-GM (whole tumor cell vaccine)
• Tumor implantation: 5 × 103 cells, right frontal lobe
• GL-GM: 2 × 106 irradiated (40 Gy) GL261-GMCSF cells, on d5, d19, and d33, IP
• TMZ:
 - Systemic (SC): 50 mg/kg, at d7, d8 and d9, IP
 - Local (LC): 4.2 mg/kg/day, from d7 to d9, intratumoral
• Local administration of TMZ induced a higher survival rate than systemic administration, and the effect was T cell-dependent
• SC but not LC TMZ depleted blood leukocytes
• Combination of TMZ IC and GL-GM increased survival and induced immune benefits with increased CD4 and CD8 TILs
• Immune memory was established in long-term survivors (SC TMZ + GL-GM)
Fritzell S., et al. (2013) [128]
TMZ (local)
Whole cell vaccine
• Tumor implantation: 5 × 103 cells, right frontal lobe
• Whole cell immunization: 2 × 106 irradiated (40 Gy) cells (GL261 or KR158) on d5, d19, and d33, SC
• TMZ: 180 μg administered over 3 days, starting on d7, convection-enhanced delivery (CED), intratumoral
GL261 or KR158-Luc
• CED-TMZ and the whole cell vaccine synergized in the GL261 model resulting in 93% long-term survivors
• The whole cell vaccine cured some mice of the KR158 model, and CED-TMZ prolonged median survival; however, there was no synergy between chemotherapy and immunotherapy
• CED-TMZ plus the vaccine significantly decreased tumor volume and increased the intratumoral influx of T cells in both models
Enriquez Pérez JE., et al. (2020) [129]
• Tumor implantation: 1 × 105 cells, caudate putamen
• TMZ:
 - Concurrent: 80 mg/kg, at d11, d13 and d15, IP
 - Sequential: metronomic dose (20 mg/kg) at d7–9 + 80 mg/kg at d11, d13 and d15, IP
• anti-CD47 (MIAP-140): 100 μg, at d11, d13 and d15, IP
• anti-PD-1: 100 μg, on d16, d18 and d20, IP
GL261 or CT2-A orthotopic syngeneic • Sequential TMZ treatment combined with anti-CD47 improved tumor growth inhibition and mice survival; monotherapies and concurrent treatment did not
• Combination of sequential TMZ and anti-CD47 activated immune response in vivo, with significant increase of CD4 and CD8 T cell, IFN-γ-secreting cell and activated TAM numbers
• Triple combination of TMZ, anti-CD47 and anti-PD-1 further improved the survival
von Roemeling CA., et al. (2020) [130]