Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mechanisms of Immune Suppression
2.1. Immune Checkpoints and Cancer Immunotherapies
2.1.1. PD-1 and PD-L1
2.1.2. Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4)
2.1.3. Lymphocyte-Activation Gene 3 (LAG-3)
2.1.4. T-Cell Immunoglobulin and Mucin Domain-Containing Protein 3 (TIM-3)
2.1.5. T-Cell Immunoreceptor with Immunoglobulin and ITIM Domain (TIGIT)
2.1.6. CD39/CD73/A2AR Pathway
2.1.7. V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA)
2.1.8. B7-H3/B7-H4
2.1.9. SIRPA/CD47
2.1.10. NKG2A/HLA-E/CD94
2.1.11. LILRB1/LILRB2: HLA-G
2.1.12. Sialic Acid-Binding Immunoglobulin-Type Lectins (Siglecs)
2.2. Metabolic Reprogramming to Foster an Immunosuppressive Environment
2.3. Recruitment of Immunosuppressive Cells into the Environment
2.4. Antigen Presentation
3. Cancer Immunotherapeutic Strategies
3.1. Antibody-Based Therapy
3.1.1. Immune Checkpoint Blockade (ICB)
3.1.2. Antibody–Drug Conjugates (ADCs)
3.1.3. Bispecific Antibodies (bsAb)
3.1.4. Other Monoclonal Antibody (mAb)-Based Therapies
3.2. Adoptive Cell Transfer (ACT) Therapy
3.2.1. Tumor-Infiltrating Lymphocyte (TIL) Therapy
3.2.2. Chimeric Antigen Receptor (CAR)-Based Therapy
CAR-T
CAR-NK
3.2.3. T-Cell Receptor-Engineered T Cells (TCR-Ts)
3.3. Cancer Vaccines
3.3.1. Cell-Based Cancer Vaccines
3.3.2. Peptide-Based Cancer Vaccines
3.3.3. Viral- and Bacterial-Vector-Driven Cancer Vaccines
3.3.4. Nucleic Acid-Based Cancer Vaccines
3.4. Cytokine-Based Therapies
3.5. Oncolytic Viruses (OVs)
3.6. Combined Approaches to Treat Hot, Altered, and Cold Immune Landscapes
4. Overcoming Cancer Immunotherapeutic Resistance
4.1. Alterations in the Tumor Microenvironment (TME)
4.2. Spatial Immune Cell Heterogeneity
4.3. Alterations in Antigen Presentation
4.4. Altered Signaling Pathways
5. Discussion and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Condition | Intervention | Format | Gov. Identifier | Phase | Status | Enrollment |
---|---|---|---|---|---|---|
Immune checkpoint inhibitors | ||||||
Metastatic hepatocellular carcinoma (HCC) | Cobolimab (anti Tim3), Dostarlimab (anti PD-1) | Humanized IgG4 | NCT03680508 | II | Recruiting | 42 |
Advanced solid tumor | BND-22 (anti-LILRB1) monotherapy or in combination with Pembrolizumab (anti-PD-1) or Cetuximab (anti EGFR) | Humanized IgG4 | NCT04717375 | I/II | Recruiting | 456 |
Stage IV NSCLC | Nivolumab Ipilimumab plus chemotherapy (Carboplatin Paclitaxel Pemetrexed Cisplatin) | -- | NCT03215706 | III | Active, not recruiting | 719 |
Metastatic squamous HNSCC | Durvalumab in combination with small-molecule antagonists of CXCR2 and STAT3 | IgG1 | NCT02499328 | I/II | Active, not recruiting | 340 |
Hormone-sensitive prostate cancer | Nivolumab monotherapy or in combination with BMS-986253 (anti-IL8) | -- | NCT03689699 | I/II | Active, not recruiting | 60 |
Advanced solid tumor | Uliledlimab (anti- CD73) Toripalimab (anti-PD-1) | Humanized mAb | NCT04322006 | I/II | Recruiting | 376 |
Antibody–drug conjugates | ||||||
HER2-positive and PD-L1-positive locally advanced or metastatic breast cancer | T-DM1 (Trastuzumab Emtansine) Atelizumab (anti PD-L 1) | - | NCT04740918 | III | Active, not recruiting | 96 |
Pre-treated HER2 breast cancer | T-Dxd (Trastuzumab Deruxtecan) Capecitabine Lapatinib Trastuzumab | - | NCT03523585 | III | Active, not recruiting | 608 |
Advanced solid tumor | SGN-B7H4V (B7-H4 targeted ADC) | - | NCT05194072 | I | Recruiting | 430 |
Relapsed or refractory DLBCL | Loncastuximab Tesirine in combination with Rituximab | NCT04384484 | III | Recruiting | 350 | |
Bispecific Antibodies (bsAb) | ||||||
Advanced solid tumors | IOS-1002 (anti- LILRB1, LILRB2, KIR3DL1) monotherapy or in combination with Pembrolizumab | HLA-B57-Fc fusion protein | NCT05763004 | Ia/Ib | Recruiting | 140 |
CDX585 (anti-LILRB2, PD-1) | IgG1k | NCT05788484 | I | Recruiting | 130 | |
Advanced hepatobiliary cancer | Volrustomig (anti-PD-1, CTLA-4) Or Rilvegostomig (anti-PD-1, TIGIT) as monotherapy or in combination With Carboplatin Gemcitabine Cisplatin |
IgG1 Humanized IgG1 | NCT05775159 | II | Recruiting | 260 |
High risk locally advanced cervical cancer | Volrustomig (anti- PD-1, CTLA-4) | IgG1 | NCT06079671 | III | Recruiting | 1000 |
EGFR-mutant locally advanced or metastatic non-squamous NSCLC | Ivonescimab (anti PD-1/VEGF) | Humanized IgG1 | NCT05184712 | III | Recruiting | 470 |
Refractory small cell lung cancer (SCLC) | Tarlatamab (engages DLL3, CD3) | bsTCE | NCT05060016 | II | Active, not recruiting | 222 |
Metastatic castration-resistant prostate cancer (mCRPC) | Gammabody® (engages Vγ2Vδ9, PSMA) | Bs γδTCE | NCT05369000 | I/II | Recruiting | 66 |
Other monoclonal antibodies (mAbs) | ||||||
Metastatic HCC | Humax-IL8 (anti IL-8) or Cabiralizumab (anti-CSF1-R) in combination with Nivolumab |
Humanized IgG1K -- | NCT04050462 | II | Active, not recruiting | 23 |
Treatment naïve advanced melanoma or RCC | Sotigalimab (CD40 agonist mAb)\ Nivolumab Ipilimumab | -- | NCT04495257 | I | Recruiting | 36 |
Condition | Intervention | Gov. Identifier | Phase | Status | Enrollment |
---|---|---|---|---|---|
CAR-T | |||||
GD2-expressing brain tumor | GD2 CAR-T | NCT03373097 | I | Recruiting | 34 |
CLDN6-positive relapsed or refractory advanced solid tumors | CLDN6 CAR-T CLDN6 uRNA-LPX/CLDN6 modRNA-LPX (mRNA vaccine) | NCT04503278 | I/IIa | Recruiting | 145 |
Children with recurrent/refractory malignant brain tumors | IL13Ralpha2 targeting Hinge-optimized 41BB-co-stimulatory CD19-CAR-T Fludarabine Cyclophosphamide | NCT04510051 | I | Recruiting | 18 |
Multiple myeloma | SLAMF7 CAR-T BCMA CAR-T Bortezomib Dexamethasone Lenalidomide Cyclophosphamide Fludarabine | NCT04499339 NCT04923893 | I/IIa III | Recruiting | 38 650 |
CD30+ refractory/relapsed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) | CD30 CAR-T | NCT02690545 | Ib/II | Recruiting | 40 |
Relapsed or refractory B-cell lymphoma | CD19-CD22 CAR-T | NCT04715217 | I/II | Recruiting | 24 |
Malignant pleural disease | Mesothelin CAR-T Cyclophosphamide Pembrolizumab | NCT02414269 | I/II | Active, not recruiting | 113 |
CD70-expressing cancers | CD70 CAR-T | NCT02830724 | I/II | Recruiting | 124 |
CAR-NK | |||||
Stage IV ovarian cancer, refractory testis cancer, recurrent endometrial cancer CAR NK | CLDN6 targeting CAR-NK cells | NCT05410717 | I/IIa | Recruiting | 200 |
Metastatic locally advanced gastric/GEJ cancer or HNSCC | PD-L1 t-haNK N-803 Pembrolizumab (anti-PD-1) | NCT04847466 | II | Recruiting | 55 |
Relapsed/refractory NHL, CLL) or B-cell acute lymphoblastic leukemia (B-ALL) | Allogenic CD19-CAR-NK | NCT05020678 | I | Recruiting | 150 |
Refractory metastatic colorectal cancer | NKG2D CAR-NK | NCT05213195 | I | Recruiting | 38 |
CAR-Gamma Delta T cells | |||||
B-cell malignancy | CD20 Allogenic Gamma Delta CAR-T Fludarabine Cyclophosphamide | NCT04735471 | I | Recruiting | 78 |
TCR-T | |||||
Induction therapy prior to definitive treatment (chemoradiation or surgery) of locoregionally advanced HPV-associated cancers | Conditioning, E7 TCR-T cells Aldesleukin (IL-2) | NCT05639972 | I/II | Recruiting | 15 |
TCR against neoantigens in subjects with relapsed/refractory solid tumors (gynecologic colorectal, pancreatic, NSCLC, ovarian cancer) | Neoantigen-specific TCR-T cell Aldesleukin | NCT05194735 | I/II | Active, not recruiting | 180 |
Previously untreated advanced melanoma | PRAM (PReferentially expressed antigen in Melanoma) TCR-T Nivolumab (anti PD-1) Nivolumab + Relatlimab (anti LAG3) | NCT05122221 | III | Recruiting | 12 |
Refractory mesothelin-expressing mesothelioma (MPM), ovarian cancer (OvC), cholangiocarcinoma (CHO), or NSCLC | Gavocabtagene autoleucel (Mesothelin targeted TCR-T) Fludarabine Cyclophosphamide Nivolumab Ipilimumab | NCT03907852 | II | Recruiting | 175 |
KRAS G12V-expressing solid tumors | KRAS G12V targeted TCR-T | NCT06105021 | I/II | Recruiting | 100 |
Tumor-Infiltrating Lymphocyte (TIL) therapy | |||||
Metastatic CRC, ovarian, pancreatic, and breast cancer | Young TIL Pembrolizumab Aldesleukin Chemotherapy | NCT01174121 | II | Recruiting | 332 |
Recurrent, metastatic, or persistent cervical carcinoma | Autologous TIL (IL-145) Pembrolizumab IL-2 | NCT03108495 | II | Recruiting | 189 |
Condition | Intervention | Adjuvant | Covt. Identifier | Phase | Status | Enrollment |
---|---|---|---|---|---|---|
mRNA vaccine | ||||||
Advanced melanoma | Neoantigen mRNA Pembrolizumab | - | NCT05933577 | III | Recruiting | 1089 |
TriMix DC (MAGE-A3, MAGE-C2, tyrosinase and gp100) Ipilimumab | CD70, CD40 ligand, TLR4 | NCT01302496 | II | Recruiting | 39 | |
Neoantigen mRNA Pembrolizumab | -- | NCT03815058 | II | Recruiting | 131 | |
Resected Stage II (High Risk) and Stage III CRC | Neoantigen mRNA Pembrolizumab | - | NCT04486378 | II | Recruiting | 201 |
Unresectable recurrent or metastatic HPV16+ HNSCC | HPV 16 E6 and E7 mRNA Pembrolizumab | - | NCT04534205 | II | Recruiting | 285 |
NSCLC | NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1 mRNA Durvalumab | - | NCT03164772 | I/II | Recruiting | 61 |
Advanced malignant solid tumors. | Neoantigen mRNA | - | NCT05198752 | I | Recruiting | 30 |
DNA vaccine | ||||||
Advanced hepatocellular carcinoma | Neoantigen DNA | Plasmid Encoded IL-12 | NCT04251117 | I/IIa | Recruiting | 36 |
CRC | OncoMimics™ peptides, UCP2 Nivolumab | Montanide | NCT05350501 | II | Recruiting | 34 |
Resectable HPV Type 16- and/or 18-positive head and neck cancer | HPV16/18 E6/E7 DNA | Flt3L | NCT05286060 | II | Recruiting | 25 |
Early stage TNBC | MDM2, YB1, SOX2, CDC25B, CD105 plasmid | GM-CSF | NCT05455658 | II | Recruiting | 33 |
Peptide vaccine | ||||||
IIIC-IV melanoma or hormone receptor-positive Her2-negative metastatic refractory breast cancer | Neoantigen peptide Nivolumab | Poly ICLC | NCT05098210 | I | Recruiting | 20 |
Advanced solid tumor | Neoantigen peptide Pembrolizumab | -- | NCT05269381 | I | Recruiting | 36 |
Condition | Intervention | Govt. Identifier | Phase | Status | Enrollment |
---|---|---|---|---|---|
Oncolytic viruses | |||||
Pancreatic adenocarcinoma, ovarian, biliary, and colorectal cancer | LOAd703 (oAD/CD40L-4-1BBL) | NCT03225989 | I/II | Active not, recruiting | 46 |
Metastatic pancreatic cancer | VCN-01(oAD/HA) Nab-Paclitaxel Gemcitabine | NCT05673811 | II | Active not, recruiting | 96 |
Localized prostate cancer | ProstAtak (aglatimagene besadenovec + Valacyclovir | NCT01436968 | III | Active, not recruiting | 711 |
Engineered cytokines | |||||
Metastatic castration sensitive and castration-resistant prostate cancer | NHS-IL12 (IL-12 molecules fused to anti-NHS76) | NCT04633252 | I/II | Recruiting | 86 |
Advanced Kaposi sarcoma | NHS-IL12 monotherapy or in combination with M7824 (anti PD-L1/TGFβ TRAP) | NCT04303117 | I/II | Recruiting | 64 |
Locally advanced or metastatic solid tumors | IL-15–IL-15Rα (sushi) heterodimer (IL15 superagonist) | NCT04250155 | I | Recruiting | 250 |
Advanced solid tumor | Pegilodecakin (PEG-rIL-10) | NCT02009449 | I | Active, not recruiting | 350 |
Combination Agent | Conditions |
---|---|
Nivolumab + Ipilimumab | Metastatic melanoma, advanced RCC, MSI-H or dMMR metastatic CRC, advanced HCC, metastatic NSCLC (PD-L1 tumor expression ≥1%), unresectable malignant pleural mesothelioma, metastatic ESCC |
Nivolumab + Chemotherapy | Metastatic ESCC, metastatic gastric cancer Neo |
Nivolumab + Ipilimumab + 2 Cycles of Platinum-Doublet chemotherapy | First-line metastatic or recurrent NSCLC, esophageal or GEJ carcinoma |
Nivolumab + Relatlimab-rmbw | Unresectable/metastatic melanoma |
Pembrolizumab + Chemotherapy | HNSCC, metastatic SCLC, high-risk early-stage and locally recurrent unresectable/metastatic TNBC, advanced unresectable/metastatic HER2-negative GEJ adenocarcinoma, first-line metastatic non-squamous NSCLC, locally advanced unresectable/metastatic BTC |
Pembrolizumab + Chemoradiotherapy | FIGO 2014 Stage III-IVA cervical cancer |
Pembrolizumab + Axitinib | First-line advanced RCC |
Pembrolizumab + Lenvatinib | Non-MSI-H or dMMR advanced endometrial carcinoma, first-line advanced RCC |
Pembrolizumab + Chemotherapy + Bevacizumab | Metastatic cervical cancer |
Pembrolizumab + Trastuzumab + Chemotherapy | First-line locally advanced unresectable/metastatic PD-L1-positive HER2-positive GEJ adenocarcinoma |
toripalimab-tpzi + Chemotherapy | Metastatic or recurrent, locally advanced NPC |
Durvalumab + Chemotherapy | Locally advanced or metastatic BTC |
Durvalumab + Chemoradiotherapy | Unresectable Stage III NSCLC |
Atezolizumab + Bevacizumab + Chemotherapy | First-line metastatic non-squamous NSCLC |
Atezolizumab + Bevacizumab | First-line unresectable HCC |
Atezolizumab + chemotherapy | First-line Extensive stage SCLC, metastatic NSCLC without EGFR/ALK aberrations Metastatic TNBC |
Atezolizumab + Cobimetinib + Vemurafenib | BRAFV600 mutation-positive advanced melanoma |
Avelumab + Axitinib | Advanced RCC |
Avelumab + Chemotherapy | Locally advanced or metastatic UC |
Tremelimumab + Durvalumab | Unresectable HCC |
Tremelimumab + Durvalumab + Chemotherapy | Metastatic NSCLC |
Daratumumab + bortezomib + dexamethasone + thalidomide | MM |
Elotuzumab + Lenalidomide + Dexamethasone | Newly diagnosed MM |
Efortumab vedotin-ejfv (ADC) + Pembrolizumab | Locally advanced or metastatic UC |
Polatuzumab vedotin + Rituximab + Chemotherapy | previously untreated DLBCL |
Anti-PD-1 (Nivolumab, Pembrolizumab, Toripalimab-tpzi), anti-CTLA-4 (Ipilimumab, Tremelimumab), anti-PD-L1 (Atezolizumab, Avelumab, Durvalumab), anti-LAG3 (Relatlimab), anti-VEGF (Bevacizumab), anti-HER2 (Trastuzumab), anti-CD38 (Daratumumab), anti-SLAMF7 (Elutuzumab), CD-79b directed ADC (Polatuzumab vedotin) |
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Mitra, A.; Kumar, A.; Amdare, N.P.; Pathak, R. Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion. Biology 2024, 13, 307. https://doi.org/10.3390/biology13050307
Mitra A, Kumar A, Amdare NP, Pathak R. Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion. Biology. 2024; 13(5):307. https://doi.org/10.3390/biology13050307
Chicago/Turabian StyleMitra, Ankita, Anoop Kumar, Nitin P. Amdare, and Rajiv Pathak. 2024. "Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion" Biology 13, no. 5: 307. https://doi.org/10.3390/biology13050307