Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives
Abstract
:1. Introduction
2. Single Immune Therapies are not Effective in Glioblastoma
2.1. Immune Checkpoint Inhibitors
2.1.1. PD-1 Inhibitor Trials
2.1.2. PD-L1 Inhibitor Trials
2.2. Vaccination with Peptides or Dendritic Cells
2.2.1. Peptide Vaccination Trials
2.2.2. DC Vaccination Trials
2.3. Adoptive Transfer of Effector Lymphocytes
2.3.1. Gene-Engineered T cells
2.3.2. Non-Engineered T Cells and Other Lymphocytes
3. Immune Therapy Resistance in Glioblastoma
3.1. Low-Immunogenicity of Glioblastoma
3.2. Immune Privilege of CNS
3.3. Immune-Suppressive Micro-Environment
3.3.1. Immune-Suppressive Cells
3.3.2. Immune-Suppressive Mediators
4. Strategies to Sensitize Glioblastoma to Immune Therapies
4.1. Strategies to Enhance the Efficacy of ICI
4.1.1. Downregulating the Immune Suppressive Micro-Environment
4.1.2. Increasing the CD8 T Cell Influx
4.2. Strategies to Enhance the Efficacy of Vaccinations
4.3. Strategies to Enhance the Efficacy of Adoptive Transfer of Effector Lymphocytes
4.4. Combination of ICI, Vaccination, and Adoptive Transfer of Effector Lymphocytes
5. Outstanding Questions for Future Research
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Clinical Trial | Phase | Target | Treatment | Control | Indication | # Patients | Endpoint | Outcome |
---|---|---|---|---|---|---|---|---|
CheckMate 143 NCT02017717 PMC5463583 | III | PD-1 | Nivolumab | Bevacizumab | R GB | Each arm: ~185 | OS | No impact |
CheckMate 498 NCT02617589 | III | PD-1 | RT, nivolumab | SOC | P GB MGMT-unmeth. | Each arm: ~275 | OS | No impact |
CheckMate 548 NCT02667587 | II | PD-1 | SOC, nivolumab | SOC, placebo | P GB MGMT-meth. | Each arm: ~160 | PFS | No impact |
Neo-nivo NCT02550249 30742120 | II | PD-1 | Nivolumab (neo-adjuvant), (S)S, nivolumab (adjuvant) | None | P GB R GB | P: 3 R: 27 | (OS) | 7.3 mo |
NCT02337491 | II | PD-1 | Pembrolizumab, bevacizumab | Pembrolizumab | R GB | Treatment: 50 Control: 30 | (OS) | 8.8 mo vs. 10.3 mo |
NCT02337686 | II | PD-1 | SS, pembrolizumab | None | R GB | 15 | PFS6 | 53% |
NCT02852655 30742122 | II | PD-1 | Pembrolizumab (neo-adjuvant), SS, pembrolizumab (adjuvant) | SS, pembrolizumab (adjuvant) | R HGG | Treatment: 16 Control: 19 | (OS) | 13.7 mo vs. 7.5 mo |
NCT03291314 | II | PD-L1 | Avelumab, axitinib | None | R GB | 32 | PFS6 | 18% |
SEJ NCT03047473 | II | PD-L1 | SOC, avelumab | None | P GB | 24 | (PFS) | 11.9 mo |
NCT02336165 | II | PD-L1 | SOC, durvalumab | Historical | P GB MGMT-unmeth. | 40 | OS12 | 60% vs. 50% |
Clinical Trial | Phase | Target | Treatment | Control | Indication | # Patients | Endpoint | Outcome |
---|---|---|---|---|---|---|---|---|
HSPPC-96 NCT00905060 | II | Autologous peptides | SOC, PEP | None | P GB | 46 | OS | 23.8 mo |
HSPPC-96 NCT00293423 24335700 | II | Autologous peptides | SS, PEP | None | R GB | 41 | OS6 | 90.2% |
HSPPC-96 NCT01814813 | II | Autologous peptides | PEP Bevacizumab | Bevacizumab | R GB | 30 | OS | No impact |
ACT-IV NCT01480479 28844499 | III | EGFRvIII | SOC, PEP | SOC, KLH | P GB EGFRvIII+ | 371 | OS | No impact |
ACT-III 25586468 | II | EGFRvIII | SOC, PEP | Historical | P GB EGFRvIII+ | 65 | PFS5.5 | 66% vs. 45% |
ACT-II 21149254 | II | EGFRvIII | SOC, PEP | Historical | P GB EGFRvIII+ | 22 | (OS) | 23.6 vs. 15.0 mo |
ReACT NCT01498328 | II | EGFRvIII | PEP Bevacizumab | KLH Bevacizumab | R GB EFGRvIII+ | 33 | PFS6 | 27% vs. 11% |
ACTIVATe NCT00643097 20921459 | II | EGFRvIII | SOC, PEP | Historical | P GB EGFRvIII+ | 18 | PFS6 | 94% vs. 59% |
ITK-1 UMIN000006970 30500939 | III | Multiple TAA | PEP | Placebo | R GB HLA-A24+ | Treatment: 58 Control: 30 | OS | No impact |
SL-701 NCT02078648 | II | Multiple TAA | PEP Bevacizumab | None | R GB HLA-A2+ | 74 | OS12 | 43% |
IMA-950 NCT01920191 30753611 | I/II | Multiple TAA | SOC, PEP | None | P GB HLA-A2+ | 16 | (OS) | 19 mo |
SurVaxM~ NCT02455557 | II | Survivin | SOC, PEP | None | P GB HLA-A2, -A3, -A11 and -A24+ | 55 | OS12 | 70.8% |
Clinical Trial | Phase | Loading Material for DCs | Treatment | Control | Indication | # Patients | Endpoint | Outcome |
---|---|---|---|---|---|---|---|---|
NCT01567202 30159779 | II | GSC antigens | P: SOC, DC R: SS, RT/CT, DC | P: SOC, placebo R: SS, RT/CT, placebo | P GB R GB | Treatment: 22 Control: 21 | PFS | 7.7 mo vs. 6.9 mo |
NCT02772094 21715171 | I/II | Irradiated tumor cells | SOC/SS, DC | None | P GB | 16 | OS | 17 mo |
ICT-107 NCT01280552 31320597 | II | Multiple TAA | SOC, DC | SOC, placebo | P GB HLA-A1+ and/or -A2+ | Treatment: 81 Control: 43 | OS | 17.0 vs. 15.0 mo |
DCVax-L NCT00045968 29843811 | III | Tumor lysate | SOC, DC | SOC, placebo | P GB | 331 | (OS) | 23.1 mo |
GBM-Vax NCT01213407 30301187 | II | Tumor lysate | SOC, DC | SOC | P GB | 34 | PFS12 | No impact |
NCT03879512 30054667 | I/II | Tumor lysate | SS, Cyclophosphamide, DC | None | R GB pediatric R GB adult | Pediatric: 6 Adult: 5 | OS6 | 100% |
DEND/GM NCT01006044 28499389 | II | Tumor lysate | SOC, DC | None | P GB | 31 | PFS | 12.7 mo |
NCT00576537 18632651 | I/II | Tumor lysate | SOC/SS, DC | None | P GB R GB | P: 11 R: 23 | (OS) | Vaccine responders: 21 mo Nonresponders 14 mo |
NCT00323115 21499132 | II | Tumor lysate | SOC, DC | None | P GB | 10 | (OS) | 28 mo |
DENDR2 NCT02820584 | I/II | Tumor lysate | (1) SS, TMZ, DC (2) SS, TTX, DC | None | R GB | (1) 12 (2) 8 | (OS) | (1) 7.4 mo (2) 9.2 mo |
DENDR1 29632727 | I/II | Tumor lysate | SOC, TMZ, DC | None | P GB | 24 | PFS12 | 41% |
DC-CAST-GBM NCT00846456 23817721 | I/II | Tumor stem cell mRNA | SOC, DC | None | P GB | 7 | (OS) | 25 mo |
Clinical Trial | Phase | CAR Generation | Target | Other Treatment | Indication | # Patients | OR (%) | CR (%) |
---|---|---|---|---|---|---|---|---|
NCT00730613 26059190 | I | First CD3z | IL13Rα2 | SS | R GB | 3 | 0/3 (0) | 0/3 (0) |
NCT02208362 28029927 | I | Second 41BB-CD3z | IL13Rα2 | SS | R GB IL13Rα2+ | 1 | 1/1 (100) | 1/1 (100) |
NCT01109095 28426845 | I | Second CD28-CD3z | HER2 CMV pp65 | SS | R GB HER2+ | 17 | 1/17 (6) | 0/17 (0) |
NCT02209376 28724573 | I | Second 41BB-CD3z | EGFRvIII | SS | R GB EGFRvIII+ | 10 | 0/10 (0) | 0/10 (0) |
NCT01454596 30882547 | I | Third CD28-41BB-CD3z | EGFRvIII | Cyclophosphamide, Fludarabine, IL-2 | R GB EGFRvIII+ | 18 | 0/18 (0) | 0/18 (0) |
Clinical Trial | Phase | Lymphocytes | Other Treatment | Indication | # Patients | OR (%) | CR (%) | OS |
---|---|---|---|---|---|---|---|---|
9390198 | I | Alloreactive CTLs | SS, IL-2 | R A, O grade III-IV | 5 | 0/5 (0) | 0/5 (0) | - |
24795429 | I | Autologous CMV-specific T cells | CT | R GB CMV seropositive | 11 | 0/11 (0) | 0/11 (0) | - |
NCT01588769 29511178 | I | Autologous CTLs and NK cells | None | R GB | 10 | 3/10 (30) | 0/10 (0) | - |
9647171 | I | Autologous T lymphocytes | Irradiated tumor cell vaccination | R A grade III-IV | 10 | 3/10 (30) | 0/10 (0) | - |
NCT00004024 16817692 | II | Autologous T lymphocytes | Irradiated tumor cell vaccination | R A or O grade II-IV | 19 | 8/19 (42) | 1/19 (5) | - |
10778730 | I | Autologous TILs | SS, IL-2 | R GB | 6 | 3/6 (50) | 1/6 (17) | - |
NCT00331526 19816190 | II | Autologous LAK cells | SOC, IL-2 | P GB | 33 | NR | NR | 20.5 mo |
NCT00003067 8625188 | I | Autologous LAK cells | SS, IL-2 | R GB R A grade III | 19 | 4/19 (21) | 2/19 (11) | - |
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Weenink, B.; French, P.J.; Sillevis Smitt, P.A.E.; Debets, R.; Geurts, M. Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives. Cancers 2020, 12, 751. https://doi.org/10.3390/cancers12030751
Weenink B, French PJ, Sillevis Smitt PAE, Debets R, Geurts M. Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives. Cancers. 2020; 12(3):751. https://doi.org/10.3390/cancers12030751
Chicago/Turabian StyleWeenink, Bas, Pim J. French, Peter A.E. Sillevis Smitt, Reno Debets, and Marjolein Geurts. 2020. "Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives" Cancers 12, no. 3: 751. https://doi.org/10.3390/cancers12030751