Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer
Abstract
:1. Introduction
2. Immune Responses in Ovarian Cancer
2.1. Importance of the Immune Contexture in Cancer
2.2. Adaptive Immune Responses in EOC
2.3. Innate Immunity in the Context of EOC
3. Preclinical Investigations for the Development of Effective Immunotherapies in Ovarian Cancer
3.1. Use of Mouse Models for the Design of Immunotherapies
3.2. Preclinical Assessment of Immunotherapies
4. Clinical Status of Immunotherapy Efficacy in Ovarian Cancer
4.1. Immune Checkpoint Blockade Monotherapy
4.2. Immune Checkpoint Blockade Combination Strategies
4.3. Vaccine Strategies
4.4. Adoptive T-Cell Transfer
4.5. Agents Targeting the Epigenome
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study | Phase | Drug | Population | N | ORR (%) | Stable Disease | PFS Months | OS Months | Grade 3/4 Toxicity (%) |
---|---|---|---|---|---|---|---|---|---|
Anti-PD-1 | |||||||||
Matulonis et al. [204] | II | Pembrolizumab | Refractory/recurrent OC Cohort A | 376 | 8 | 29.3 | 2.1 | 19.7 | |
<3 lines, PFI 3–12 months Cohort B | 285 | 7.4 | 10.5 | 2.1 | NR | ||||
4–6 lines, PFI > 3 months | 100 | 9.9 | 27.5 | 2.1 | 17.6 months | ||||
Hamanishi et al. [206] | II | Nivolumab | Recurrent/persistent OC 1 to 3 lines PFI < 12 months | 20 | 15 | 30 | 3.5 | 20 | 40 |
Zamarin et al. [207] | II | Nivolumab | Recurrent/persistent OC 1 to 3 lines | 100 | 12 | 29 | 2 | 21.8 | 33 |
Nivolumab and Ipilimumab | PFI < 12 months | 31.4 | 39 | 3.9 | 28.1 | 49 | |||
Anti-PD-L1 | |||||||||
Disis et al. [205] | Ib | Avelumab | Recurrent OC >3 lines (64.8%) | 125 | 9.6 | 42.4 | 10.2% at 12 months | 11.2 | 7.2 |
Brahmer et al. [208] | I | BMS-936559 | >1line | 17 | 6 | 18 | 22% at 24 weeks | 9 | |
Anti-CTAL4 | |||||||||
Hodi et al. [209] | I | Ipilimumab | >1 line and GVAX vaccination (GM-CSF) | 9 | 10 | 33 | 22 |
Study | N | Arms | Primary Endpoint | Recruitment Status |
---|---|---|---|---|
Frontline setting | ||||
GINECO FIRST-ENGOT Ov44 (NCT03740165) | 912 | Arm 1: CT + Bev + Placebo followed by Placebo Arm 2: CT + Placebo Followed by Placebo + Niraparib Arm 3: CT + Dostarlimab followed by Dostarlimab+Niraparib | PFS | Recruiting |
AGO DUO-ENGOT (NCT03737643) | 1056 | Arm 1: CT + Bev + Placebo followed by Bev + Placebo Arm2: CT + Bev + Durvalumab followed by Bev + Durvalumab+Placebo Arm3: CT + Bev + Durvalumab followed by Bev + Durvalumab + Olaparib | PFS in non tBRCAmut | Recruiting |
KELYNK-001 EBOGT-Ov43 (NCT03740165) | 1086 | Arm 1: CT + Placebo followed by Placebo +/- Bev Arm 2: CT + Pembrolizumab followed by Placebo +/- Bev Arm 3: CT+Pembrolizumab followed by Pembrolizumab + Olaparib +/- Bev | PFS and OS | Recruiting |
ATHENA (NCT03522246) | 1012 | Arm 1: CT followed by Placebo Arm 2: CT followed by Rucaparib + Placebo Arm 3: CT followed by Nivolumab + Placebo Arm 4: CT followed by Rucaparib + Nivolumab | PFS | Recruiting |
IMagyn 50 GOG3015-ENGOT 0v39 (NCT 03038100) | 1300 | Arm 1: CT + Bev + Placebo Arm 2: CT+ Bev+ Atezolizumab | PFS, OS PSF and OS assessed by PD-L1 | Active Not recruiting |
Recurrent platinum-sensitive disease | ||||
ATALANTE/ENGOT Ov29 (NCT02891824) | 405 | Arm1: Placebo + Bev + platinum-based chemotherapy. Arm 2: Atezolizumab + Bev + platinum-based chemotherapy | PFS | Active, not recruiting |
ANITA/GEICO 69/ENGOT Ov41 (NCT03598270) | 414 | Arm 1: Carboplatin + Niraparib Arm 2: Carboplatin + Niraparib + Atezolizumab | PFS | Recruiting |
Recurrent platinum resistant | ||||
EORTC -1508 (NCT02659384) | 160 | Arm 1: Bev + Atezolizumab Arm 2: Bev + Atezolizumab + aspririn | PFS at 6 months | Recruiting |
Study (NCT) | Phase | Type of Vaccine | N | Population | Primary Objective | Recruitment Status |
---|---|---|---|---|---|---|
NCT01536054 | I | ALVAC(2)-NY-ESO-1 (M)/TRICOM vaccine with sirolimus | 42 | Stage II–IV ovarian, FT or primary peritoneal cancer | Safety | Completed |
NCT00616941 | I | NY-ESO-1 OLP4 + Montanide + Poly-ICLC | 28 | Stage II–IV and recurrent disease ovarian, FT or primary peritoneal cancer | Safety | Completed |
NCT00112957 | I/II | Recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1) and recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) | 23 | Ovarian, FT or primary peritoneal cancer with NY-ESO-1 or LAGE-1 expression | 12 months DFS | Completed |
NCT02166905 | I | IDO1 inhibitor INCB024360 in combination with DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly ICLC | 62 | Ovarian, FT or primary peritoneal cancer in remission after CT for primary or recurrent disease | Safety Toxicity PFS | Recruiting |
NCT00948961 | I/II | CDX-1401 in combination with Resiquimod and/or Poly-ICLC | 70 | Ovarian cancer and other solid tumors with NY-ESO-1 expression | Safety | Completed |
NCT01673217 | I | Decitabine, NYESO-I protein mixed with montanide and (GM-CSF) | 18 | Recurrent ovarian, FT or primary peritoneal cancer | Safety | Completed |
NCT02432378 | I/II | Cisplatin + CKM + Celecoxib + DC intranodal vaccine | 25 | Recurrent platinum-sensitive ovarian cancer | Safety, CD8 in the peritoneal cavity | Recruiting |
NCT03029403 | II | DPX-Survivac Vaccine+pembrolizumab + cyclophosphamide | 42 | Ovarian, FT or primary peritoneal cancer after first line | ORR | Recruiting |
NCT02759588 | I/II | GL-ONC1 +/− chemotherapy +/− Bevacizumab | 64 | Resistant/refractory | Safety, PFS, Ca125, ORR | Recruiting |
Target | Study (NCT) | Phase | N | Population | Protocol | Primary objective | Recruitment Status |
---|---|---|---|---|---|---|---|
MUC-16 | NCT02498912 | I | 30 | Recurrent MUC16 + solid tumors | Cyclophosphamide followed by Iv ip infusion of MUC16 specific T-cells secreting IL-12 | Safety | Recruiting |
HER2 | NCT00194714 | I/II | 26 | HLA2 Stage IV HER2 + breast/OC | HER2 peptide vaccination | Safety | Active, not recruiting |
NCT00228358 | I | 8 | Metastatic HER2 tumors previously vaccinated | Cyclophosphamide or denileukin diftitox followed by Expanded HER2-specific T-cells | Feasibility Safety | Completed | |
WT1 | NCT00562640 | I | 21 | Recurrent WT + OC, FT, PPC | WT-1 specific T-cells | Safety and tolerability | Active, not recruiting |
Mesothelin | NCT02580747 | II | 20 | Refractory recurrent mesothelin+ OC | Anti-meso-CAR T-cells | Safety, feasibility. Duration meso- | Unknown |
NCT03054298 | I | 30 | Recurrent mesothelin+ OC | huCART-meso cells | CAR T-cells Safety, feasibility | Active, not recruiting Terminated | |
NCT01583686 | I | 136 | Metastatic mesothelin + cancer | Lymphodepletion followed by Anti-meso-CAR T-cells | Safety, ORR | Completed | |
NCT02159716 | I | 24 | Metastatic mesothelin + cancer | Anti-meso-CAR T-cells +/-cyclophosphamide | Safety and feasibility | ||
CD133 | NCT02541370 | I | 20 | CD-33 + Refractory Cancers | Anti-CD133-CAR T-cells | Safety | Completed |
MAGE-A4 | NCT03132922 | I | 42 | HLA2+ with MAGE-A4 cancer Persistent disease | Anti-MAGE-A4c¹º³² T-cells | Safety, duration of Anti-MAGE4 T-cells | Recruiting |
NY-ESO-1 | NCT03159585 | I | 20 | HLA-A 0201+ patients with solid tumors NYESO-1+ | NY-ESO-1- T-cells (TAEST16001) | Safety | Completed |
NCT01567891 | I/II | 9 | HLA A 0201, HLA-A 0205, and/or HLA-A 0206 recurrent OC < 2lines | NYESO-1c259 T-cells | Safety | Completed | |
NCT03017131 | I | 12 | Recurrent/refractory OC | Autologous NY-ESO-1 T-cell + decitabine + IL-2 | Safety and tolerability | Recruiting | |
NCT00101257 | I | 18 | HLA DPB 0401, DPB1 0201, DRB1 07 with Stage III/IV | Autologous CD4-positive antigen-specific T-cells | Safety, toxicity, duration in vivo infused T-cells | Recruiting | |
NCT02166905 | I/IIb | 64 | NYESO-1+OC NY-ESO-1 or LAGE-1 + primary or recurrent OC | EC-205/NY-ESO-1 Fusion Protein CDX-1401, Poly ICLC, and IDO1 Inhibitor INCB024360 | Safety, PFS | Recruiting | |
Neoantigens | NCT03412877 | I/II | 210 | Metastatic/refractory solid cancer with measurable disease | Autologous T-cells engineered to express TCR Anti-Neoantigens | ORR | Recruiting |
Target | Study (NCT) | Phase | N | Population | Protocol | Primary Objective | Results |
---|---|---|---|---|---|---|---|
Decitabine | NCT00887796 | I | 12 | Recurrent OC | Decitabine+ NYESO-I protein with montanide + GM-CSF+ liposomal doxorubicin | Safety | Well-tolerated DNA Hypomethylation/ blood, circulating DNAs NY-ESO-1 Ab and T-cell responses SD 50%, PR 10% |
Entinostat | NCT02915523 | I/II | 140 | Recurrent OC >2 lines CT | Avelumab With or Without Entinostat | Dose Efficacy (PFS) | NR |
Guadecitabine | NCT02901899 | II | 38 | Recurrent OC > 1 ≤ 3 lines | Guadecitabine + Pembrolizumab | ORR | NR |
Guadecitabine | NCT03206047 | I/IIb | 75 | Platinum-resistant recurrent OC | Atezolizumab, Guadecitabine, and CDX-1401 Vaccine | Safety Efficacy (PFS) | NR |
Guadecitabine SGI-110-02 | NCT01696032 | I/II | 100 | Platinum-resistant recurrent OC | SGI-110-02 + Carboplatin or CT | Efficacy (PFS) | 6-month PFS rate increased in the Guadecitabine group (37% vs. 11%) |
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Martinez, A.; Delord, J.-P.; Ayyoub, M.; Devaud, C. Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer. Cancers 2020, 12, 1761. https://doi.org/10.3390/cancers12071761
Martinez A, Delord J-P, Ayyoub M, Devaud C. Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer. Cancers. 2020; 12(7):1761. https://doi.org/10.3390/cancers12071761
Chicago/Turabian StyleMartinez, Alejandra, Jean-Pierre Delord, Maha Ayyoub, and Christel Devaud. 2020. "Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer" Cancers 12, no. 7: 1761. https://doi.org/10.3390/cancers12071761