Revolutionization in Cancer Therapeutics via Targeting Major Immune Checkpoints PD-1, PD-L1 and CTLA-4
Abstract
:1. Introduction
2. Emerging Immune Checkpoint Inhibitors
2.1. CTLA-4 (CD152) Inhibitors
2.2. PD-1 (CD279) Inhibitors
2.3. PD-L1 (CD274) Inhibitors
3. Immune Checkpoint Inhibitors in Combination with ICDs (Immunogenic Cell Death) Inducers
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
PD-1/PD-L1 | programmed death 1/programmed death ligand 1 |
CTLA-4 | cytotoxic T lymphocyte-associated antigen-4 |
IDO | indoleamine 2.3-dioxygenase |
HER2+ | human epidermal growth factor receptor 2 |
SCLC | small cell lung cancer |
TNF-α | tumor necrosis factor-α |
CSCC | cutaneous squamous cell carcinoma |
NCI | National Cancer Institute |
FDA | Food and Drug Administration |
CTLs | cytotoxic T lymphocytes |
CTLA-4 | cytotoxic T lymphocyte-associated protein 4 |
ROS | reactive oxygen species |
IR | immune response |
TCR | T cell receptor |
TRIM | T cell interacting molecules |
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Cancer | FDA Approved Agents | Clinical Trial (s) |
---|---|---|
Merkel cell carcinoma (Skin cancer) | Avelumab (2017) | JAVELIN phase 2 |
Pembrolizumab (2018) | KEYNOTE-017 phase 2 | |
Melanoma (Skin Cancer) | Pembrolizumab (2014) | KEYNOTE-001 phase 1 |
Nivolumab (2014) | CheckMate-037 | |
Nivolumab + ipilimumab (2015) | CheckMate-069 | |
Pembrolizumab (2015) | KEYNOTE-006 phase 3 | |
Nivolumab + ipilimumab (2016) | CheckMate-067 phase 3 | |
Nivolumab (2017) | CheckMate-238 phase 3 | |
Primary mediastinal large B-cell lymphoma (Blood cancer) | Pembrolizumab (2018) | KEYNOTE-170 phase 2 |
Classical Hodgkin lymphoma (Blood Cancer) | Nivolumab (2016) | CheckMate-039 phase 1 and Checkmate-205 phase 2 |
Pembrolizumab (2017) | KEYNOTE-087 phase 2 | |
Small cell lung cancer | Nivolumab (2018) | CheckMate-032 phase ½ |
Non-small cell lung cancer | Nivolumab (2015) | CheckMate-017 phase 3 |
Pembrolizumab (2015) | CheckMate-057 phase 3 | |
Atezolizumab (2016) | POPLAR phase 2 and OAK phase 3 | |
Pembrolizumab (2016) | KEYNOTE-024 phase 3 | |
Pembrolizumab + Caroplatin + Pemetrexed (2017) | KEYNOTE-024 phase 3 | |
Durvalumab (2018) | KEYNOTE-021 phase 2 | |
Pembrolizumab + Pemetrexed + Platinum (2018) | PACIFIC phase 3 KEYNOTE-189 phase 3 | |
Microsatellite instability-high and DNA mismatch repair deficiency unresectable solid tumors (Gastrointestinal Cancer) | Pembrolizumab (2017) | KEYNOTE-164 phase 2 |
Nivolumab (2017) | CheckMate-142 phase 2 | |
Nivolumab + ipilimumab (2018) | CheckMate-142 phase 2 | |
Hepatocellular carcinoma | Nivolumab (2017) | CheckMate-040 phase ½ |
Pembrolizumab (2018) | KEYNOTE-224 phase 2 | |
Gastric cancer | Pembrolizumab (2017) | KEYNOTE-059 phase 2 |
Renal cell cancer | Nivolumab (2015) | CheckMate-025 phase 3 |
Nivolumab + ipilimumab (2018) | CheckMate-025 phase 3 | |
Urothelial cancer (Renal Cancer) | Atezolizumab (2016) | IMVigor 210 phase 2 |
Nivolumab (2017) | CheckMate-275 phase 2 | |
Atezolizumab (2017) | IMVigor 210 phase 2 | |
Durvalumab (2017) | Study 1108 phase 2 | |
Avelumab (2017) | JAVELIN solid tumor phase 1 | |
Pembrolizumab (2017) | KEYNOTE-052 phase 2 KEYNOTE-045 phase 3 | |
Cervical cancer | Pembrolizumab (2018) | KEYNOTE-158 phase 2 |
Head and Neck squamous cell carcinoma | Pembrolizumab (2016) | KEYNOTE-012 phase 1b |
Nivolumab (2016) | CheckMate-141 phase 3 |
Emerging PD-1 Inhibitors | Features | Cancer Type | Reference |
---|---|---|---|
Cemiplimab | Fully human hinge stabilized IgG4 anti-PD-1 antibody | CSCC patients (both metastatic or locally advanced) | [32] |
Sintilimab | PD-1 targeted human IgG4 mAb (monoclonal antibody) | Gastric carcinoma (NCT03745170) | [33] |
Lymphoma (NCT04052659) | |||
Oesophageal carcinoma (NCT03946969) | |||
NSCLC (NCT03830411) | |||
Nasopharyngeal cancer (NCT03700476) | |||
Tislelizumab | PD-1 targeted humanized IgG4 mAb | Hodgkin’s lymphoma (both relapsed and refractory) | [34] |
Nasopharyngeal carcinoma (NCT03924986) | [35] | ||
UC (NCT03967977) | |||
Gastroesophageal or gastric junction cancer (NCT03777657) | |||
Lymphoma (NCT03493451) | |||
Oesophageal carcinoma (NCT03957590) | |||
NSCLC (NCT03358875) | |||
Toripalimab | Humanized IgG4 anti PD-1 mAb | Metastatic melanoma patients who did not respond to systemic therapies | [36] |
Liver cancer (NCT03949231) | [37] | ||
Oesophageal cancer (NCT03829969) | |||
Neck and head cancer (NCT03952065), | |||
Melanoma (NCT03941795), | |||
NSCLC (NCT03924050), | |||
Neuroendocrine carcinoma of the bladder (NCT03992911) | |||
Nasopharyngeal carcinoma (NCT03581786) | |||
Spartaliumab | IgG4 PD-1 targeted mAb | Phase III COMBI-I trial (NCT02967692) in BRAFV600 mutant metastatic or unresectable melanoma | [38] |
triple-negative breast cancer treatment (TNBC; NCT03499899) | |||
RCC (NCT04028245) | |||
NSCLC (NCT03647488) | |||
Nasopharyngeal carcinoma and colorectal cancer (NCT03891953) |
Inhibitor | Role in Cancers | References |
---|---|---|
Atezolizumab (MPDL3280) Fully humanized IgG1 monoclonal antibody having a modified Fc domain that prohibits the depletion of PD-L1 expressing T cells | It blocks PD-L1 interaction with both B7.1 and PD-1. | [45] |
Atezolizumab treatment increased immunity against tumors via reducing immunosuppressive signals present in the tumor microenvironment. | [46] | |
Highly effective against several hematologic malignancies and solid tumors. | [47] | |
Several preclinical studies have reported increased CD8+ T, IL-18, CXCL11, IFN cells, and reduced IL-6 cytokines. | [48] | |
In a phase 1 study, three dosing schedules of this drug were tested against various recurrent melanomas, renal cell carcinoma, non-small cell lung carcinoma, gastric cancer, and neck and head squamous cell cancer. In addition, phase II trials have reported a 10% overall response rate in patients with enhanced PD-L1 expression levels. | [49] | |
Atezolizumab obtained FDA approval for metastatic or local advanced urothelial cancer against cisplatin therapy in May 2016. | [50] | |
Commonly reported adverse effects include fatigue, pyrexia, reduced appetite, diarrhea, nausea, arthralgia, rash, pruritus, and headache. | ||
Obtained FDA approval in October 2016 for NSCLC patients undergoing platinum-based chemotherapy | [51] | |
In December 2018, atezolizumab obtained FDA approval for NSq NSCLC (non-squamous and non-small cell lung carcinoma) patients along with chemotherapy and bevacizumab treatments. | [52] | |
In March 2019, it obtained further FDA approval for small cell lung cancer patients and chemotherapy. Further FDA has also granted its approval for metastatic or local advanced PD-L1 + ve TNBC patients along with nab-paclitaxel treatment. | [53] | |
Durvalumab (MEDI4736) Fully humanized IgG1 monoclonal antibody that blocks the interaction of CD80 molecules with PD-1. | Potent inhibitor with subnanomolar activities against PD-L1. | [54] |
In vivo studies having co implanted T cells have shown significant inhibition of human tumor growth in a xenograft model. | [55] | |
In May 2017, FDA approved urothelial cancer patients (metastatic or locally advanced) following platinum-based chemotherapies. | [56] | |
In February 2018, durvalumab received FDA approval for unresectable NSCLC (stage III) patients undergoing platinum-based chemotherapies. | [57] | |
Avelumab (MSB0010718C) Fully humanized IgG1 mAb blocking the interaction of PD-L1 with B7.1 and PD 1 (Inhibitory T cell receptor) | Avelumab treatments result in cytokine production or adaptive or cell-mediated antitumor IR (immune response). | [58] |
The wild-type Fc region helps the NK cells induce tumor-directed ADCC (antibody-dependent cell-mediated cytotoxicity). | [59] | |
In March 2017, the FDA approved its use for patients with metastatic Merkel cell carcinoma (MCC). | [60] | |
In May 2017, the FDA approved its usage for patients with metastatic urothelial cancer following platinum-based chemotherapy. | [61] | |
In May 2019, the FDA approved its use for patients with advanced RCC (renal cell carcinoma) axitinib treatment. | [62] | |
BMS-936559 (MDX-1105) Fully humanized IgG4 mAb that inhibits binding of PD-L1with CD80 and PD-1 | Commonly reported side effects include infusion reaction, arthralgia, fatigue, rash, headache, and pruritus. | [63] |
Studies showed an overall response rate of 17% in NSCLC, RCC, and melanoma patients. | ||
CK-301 Fully humanized IgG4 mAb of IgG1 that blocks the interaction of PD-L1 with B7.1 and PD-1 | Comprises the functional Fc domain capable of ADCC induction and CDC (complement-dependent cytotoxicity) mediated Killing of PD-L1+ lymphoma cells. | [64] |
Cancer | ICD Inducers | ICIs | Anticancer Efficacy | Reference |
---|---|---|---|---|
Breast cancer | Doxil | IND (an IDO-1 inhibitor) and anti-PD-1 antibody | It induced superior synergistic anticancer response in comparison to DOX-only liposome along with reduced tumor volume | [67] |
Paclitaxel | NLG919 (an IDO-1 inhibitor) | Well-controlled tumor growth with a prolonged median survival time of mice | [68] | |
OXA | NLG919 (an IDO-1 inhibitor) | High efficiency of combined drugs over tumor growth regression compared to free medicines and prevented metastasis in tumor-bearing mice. | [69] | |
MIT | ND (an IDO-1 inhibitor) | Significant decrease in tumor size and increased survival rate in the treated animal. | [70] | |
Doxil | NLG919 (an IDO-1 inhibitor) | Increased tumor growth inhibitory potential and prolonging survival rate in treated mice. | [71] | |
Doxil | IND (an IDO-1 inhibitor) | Improved immune response and tumor regression in tumor-bearing mice | [72] | |
Ce6 (Photosensitizer) | Anti-PD-1 antibody | Increased ROS production via PDT and elevated tumor ICD; evoked immune response | [73] | |
Photosensitizer (pyrolipid, a lipid the conjugate of pyropheophorbidea) | Anti-PD-L1 antibody | Stimulated systemic immune response and distant tumors were inhibited | [74] | |
ICG | Anti-PD-L1 antibody | Prevented liver and lung metastasis via activation of antitumor immune system | [75] | |
Camptothecin + polypyrrole | Anti-PD-L1 antibody | Combined treatment-induced potent tumor immunogenic cell death and enhanced antitumor immune response. Prevented tumor recurrences and metastasis | [76] | |
DOX + Ce6 | Anti-PD-L1 antibody | Significant synergistic therapeutic effect was observed that eventually triggered the antitumor immune response and inhibited metastasis | [77] | |
Ce6 + Magnetic hyperthermia | Anti-CTLA4 Antibody | Combinatorial treatment exhibited strong anticancer activity and elicited ICD along with eradication of metastatic tumors | [78] | |
Colon Cancer | DOX | Anti-PD-1 Antibody | Treatment resulted in complete regression of persisted tumors in animals and inhibited tumor recurrence in survivors | [67] |
Ce6 | Anti-CTLA4 Antibody | This resulted in ICD induction and inhibition of distant tumors | [79] | |
DOX + photothermal reagent | Anti-PD-L1 antibody | Treatment resulted in tumor cell death and induced effective ICD. In addition, it prevented tumor growth with stimulated immune response | [80] | |
OXA + photosensitizer | Anti-PD-L1 antibody | Treatment resulted in tumor cell death and provoked ICD resulting in tumor regression via a strong immune response. | [81] | |
OXA + DHA | Anti-PD-L1 antibody | Treatment retarded tumor growth initially for one month, and no tumor recurrence was reported for about 120 days | [82] | |
OXA + PPa | Anti-CD47 Antibody | The treatment potentially inhibited tumor (both primary and abscopal) growth and inhibited tumor recurrence and metastasis | [83] | |
Prostate Cancer | Radiotherapy | Anti-PD-L1 antibody | Enhanced tumor ICD and tumor growth suppression, resulting in synergistic anticancer immune response | [84] |
IRE | IDO-1 inhibitor | Induced tumor ICD and overturned tumor immunosuppression, leading to the elimination of both secondary and primary tumors. | [85] | |
B-cell Lymphoma | DOX | IDO-1 inhibitor | Significant improvement in antitumor response in comparison to Doxil | [86] |
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Pandey, P.; Khan, F.; Qari, H.A.; Upadhyay, T.K.; Alkhateeb, A.F.; Oves, M. Revolutionization in Cancer Therapeutics via Targeting Major Immune Checkpoints PD-1, PD-L1 and CTLA-4. Pharmaceuticals 2022, 15, 335. https://doi.org/10.3390/ph15030335
Pandey P, Khan F, Qari HA, Upadhyay TK, Alkhateeb AF, Oves M. Revolutionization in Cancer Therapeutics via Targeting Major Immune Checkpoints PD-1, PD-L1 and CTLA-4. Pharmaceuticals. 2022; 15(3):335. https://doi.org/10.3390/ph15030335
Chicago/Turabian StylePandey, Pratibha, Fahad Khan, Huda A. Qari, Tarun Kumar Upadhyay, Abdulhameed F. Alkhateeb, and Mohammad Oves. 2022. "Revolutionization in Cancer Therapeutics via Targeting Major Immune Checkpoints PD-1, PD-L1 and CTLA-4" Pharmaceuticals 15, no. 3: 335. https://doi.org/10.3390/ph15030335