Beyond Anti-PD-1/PD-L1: Improving Immune Checkpoint Inhibitor Responses in Triple-Negative Breast Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. TNBC Heterogeneity and Sub-Classifications
3. Immunotherapy and Immune Checkpoint Inhibition
4. Clinical Status of ICI in TNBC
5. Improving Patient Selection
Immune Cell Signatures
6. Identifying Therapies That Will Sensitize Tumors to ICI
6.1. PI3K/AKT Pathway Inhibition
6.1.1. Isoform-Specific PI3K Inhibition
Identifier | Phase | Combination | Drug Names | Indications | Results | Ref |
---|---|---|---|---|---|---|
NCT04216472 | II | PI3Kαi + Chemo | Alpelisib + nab-PTX | Anthracycline-resistant TNBC with PIK3CA mutation or PTEN loss | Active, not recruiting | n/a |
NCT04251533 | III | PI3Kαi + Chemo | Alpelisib + nab-PTX | Advanced stage TNBC with PIK3CA mutation or PTEN loss | Active, not recruiting | n/a |
NCT05768139 | I/II | PI3Kαi (mutation specific) | STX-478 | Advanced solid tumors with PIK3CA mutation | Recruiting | n/a |
NCT01458067 | I/IIa | PI3Kβi | GSK2636771 | Solid tumors with PTEN loss | Acceptable safety/toxicity profile | [73] |
9 + NCT04439188 (MATCH-Sub-protocol P) | II | PI3Kβi | GSK2636771 | Cancers with PTEN loss | Active, not recruiting | n/a |
NCT02637531 (MARIO-1) | I/Ib | PI3Kγi +/− anti-PD1 | IPI-549 (eganelisib) +/− Nivolumab | TNBC | Acceptable safety/toxicity profile | [80] |
NCT03961698 (MARIO-3) | II | PI3Kγi + anti-PD-L1 + Chemo | IPI-549 (eganelisib) + atezolizumab + nab-PTX | Locally advanced unresectable or metastatic TNBC | Interim analysis: ORR 55.3% | [81] |
6.1.2. Pan-PI3K Inhibition and AKT Inhibition
Identifier | Phase | Combination | Drug Names | Indications | Results | Ref |
---|---|---|---|---|---|---|
NCT01790932 | II | pan-PI3Ki | BKM120 (buparlisib) | Metastatic TNBC | No OR | [82] |
NCT04345913 | I/II | pan-PI3Ki + Chemo | Copanlisib + Eribulin | Advanced stage TNBC | Active, not recruiting | n/a |
NCT01920061 | I/II | pan-PI3Ki + Chemo | Copanlisib+ Eribulin | Advanced-stage TNBC | Active, not recruiting | n/a |
NCT01090960 | I | AKTi | IPAT | Metastatic TNBC | Acceptable safety/toxicity profile | [86] |
LOTUS | II | AKTi + Chemo | IPAT + PTX | Metastatic TNBC | Trending increase OS for PTEN low and PIK3CA/AKT1/PTEN-altered subgroups (25.8 vs. 22.1 mo) | [88] |
FAIRLANE | II | AKTi + Chemo | IPAT + PTX | Early-stage TNBC | No increase in pCR | [96] |
IPATunity130 | III | AKTi + Chemo | IPAT + PTX | Locally advanced unresectable or metastatic TNBC | No improvement in PFS | [89] |
PAKT | II | AKTi + Chemo | CAPI + PTX | Metastatic TNBC | PFS (5.9 vs. 4.2 months) OS (19.1 vs. 12.6 months) | [87] |
CAPItello-290 | III | AKTi + Chemo | CAPI + PTX | Metastatic TNBC | Active, not recruiting | [97] |
NCT03742102 (BEGONIA) | Ib/II | AKTi + anti-PD-L1 + Chemo | CAPI + Durvalumab+PTX | Metastatic PD-L1+ TNBC | Interim analysis: no change in ORR | [98] |
NCT03800836 (CO40151) | Ib | AKTi + anti-PD-L1 + Chemo | IPAT + Atezolizumab + PTX or nab-PTX | Locally advanced or metastatic TNBC | Acceptable safety/toxicity profile: 73% ORR | [99] |
NCT03424005 (Morpheus-panBC) | Ib/II | AKTi + anti-PD-L1 | IPAT + Atezolizumab | Locally advanced unresectable or metastatic TNBC | Recruiting | n/a |
NCT04177108 (IPATunity170) | III | AKTi + anti-PD-L1 + Chemo | IPAT + Atezolizumab + PTX | Locally advanced unresectable or metastatic TNBC | No improvement in PFS or ORR | [67] |
NCT01263145 | Ib | AKTi + Chemo | MK-2206 + PTX | Metastatic breast cancer | Acceptable safety/toxicity profile | [100] |
NCT01277757 | II | AKTi | MK-2206 | Advanced breast cancer with PIK3CA mutation, AKT mutation, or PTEN loss | No improvement in PFS | [101] |
6.2. RAS/MAPK/ERK Pathway Inhibition
Identifier | Phase | Combination | Drug Names | Indications | Results | Ref |
---|---|---|---|---|---|---|
NCT01562275 | Ib | AKTi + MEKi | Ipatasertib + Cobimetinib | Locally advanced or metastatic solid tumors | Limited tolerability and efficacy | [108] |
NCT03202316 | II | Anti-PD-L1 + MEKi + Chemo | Atezolizumab + Cobimetinib + Eribulin | Chemotherapy-resistant metastatic inflammation breast cancer | Active, not recruiting | n/a |
NCT03801369 | II | PARPi + anti-PD-LI or MEKi or AKTi | Olaparib + Durvalumab, or Selumetinib, or Capivasertib | Metastatic TNBC | Recruiting | n/a |
6.3. High Throughput Screening to Identify Targeted Therapies
6.4. Antibody–Drug Conjugates
6.5. Chemotherapies
7. Identifying New Immunotherapy Strategies for TNBC beyond Anti-PD-1/PD-L1
7.1. CTLA-4
7.2. Targeting Alternative Checkpoints
7.3. Novel Immunotherapy Targets
7.4. Myeloid Based Therapies
8. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Bullock, K.K.; Richmond, A. Beyond Anti-PD-1/PD-L1: Improving Immune Checkpoint Inhibitor Responses in Triple-Negative Breast Cancer. Cancers 2024, 16, 2189. https://doi.org/10.3390/cancers16122189
Bullock KK, Richmond A. Beyond Anti-PD-1/PD-L1: Improving Immune Checkpoint Inhibitor Responses in Triple-Negative Breast Cancer. Cancers. 2024; 16(12):2189. https://doi.org/10.3390/cancers16122189
Chicago/Turabian StyleBullock, Kennady K., and Ann Richmond. 2024. "Beyond Anti-PD-1/PD-L1: Improving Immune Checkpoint Inhibitor Responses in Triple-Negative Breast Cancer" Cancers 16, no. 12: 2189. https://doi.org/10.3390/cancers16122189
APA StyleBullock, K. K., & Richmond, A. (2024). Beyond Anti-PD-1/PD-L1: Improving Immune Checkpoint Inhibitor Responses in Triple-Negative Breast Cancer. Cancers, 16(12), 2189. https://doi.org/10.3390/cancers16122189