Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches
Abstract
:1. Introduction
2. Overview of Immune Checkpoints
3. Pharmacological Inhibition of Immune Checkpoints
4. Combining ICIs and Anti-Tumor Vaccines
5. ICIs and Anti-Infectious Vaccines
6. Newly Emerging ICIs (Second Generation) for Combination Therapy
7. New Alternatives of Immune Checkpoint Inhibition
7.1. ASOs
7.2. Small Non-Coding RNAs
7.3. Aptamers
7.4. Peptides and Other Small-Molecule ICIs
8. Future Directions and Closing Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Target; Format | 1st Indication Approved/Reviewed | 1st EU Approval Year | 1st US Approval Year | |
---|---|---|---|---|
Ipilimumab | CTLA-4; Human IgG1 | Metastatic melanoma | 2011 | 2011 |
Pembrolizumab | PD1; Humanized IgG4 | Melanoma | 2015 | 2014 |
Nivolumab | PD1; Human IgG4 | Melanoma, non-small cell lung cancer | 2015 | 2014 |
Atezolizumab | PD-L1; Humanized IgG1 | Bladder cancer | 2017 | 2016 |
Avelumab | PD-L1; Human IgG1 | Merkel cell carcinoma | 2017 | 2017 |
Durvalumab | PD-L1; Human IgG1 | Bladder cancer | 2018 | 2017 |
Cemiplimab | PD-1; Human IgG4 | Cutaneous squamous cell carcinoma | 2019 | 2018 |
Dostarlimab | PD-1; Humanized IgG4 | Endometrial cancer | 2021 | 2021 |
Relatlimab | LAG-3; Human IgG4 | Melanoma | Review | 2022 |
Tremelimumab | CTLA-4; Human IgG2A | Antineoplastic; liver cancer | Review | Review |
Tislelizumab | PD-1; Humanized IgG4 | Esophageal squamous cell carcinoma | Review | Review |
Sintilimab | PD-1; Human IgG4 | Non-small cell lung cancer | NA | Review |
Retifanlimab | PD-1; Humanized IgG4 | Squamous cell carcinoma of the anal canal | MAA withdrawn | Review |
Penpulimab | PD-1; Humanized IgG1 | Metastatic nasopharyngeal carcinoma | NA | Review |
Omburtamab | B7-H3; Murine IgG1 | CNS/leptomeningeal metastasis from neuroblastoma | Review | Review |
Other regions | ||||
Sintilimab (Tyvyt): human anti-PD-1 mAb approved in China in December 2018 for Hodgkin’s lymphoma; Toripalimab (Tuoyi): humanized anti-PD-1 mAb approved in China in December 2018 for melanoma; Camrelizumab: humanized anti-PD-1 mAb approved in China in 2019 for Hodgkin’s lymphoma; Tislelizumab: humanized anti-PD-1 mAb, approved in China in December 2019 as a treatment for classical Hodgkin’s lymphoma; Disitamab vedotin (Aidixi): anti-HER2 humanized ADC approved in China in June 2021 as a treatment for gastric cancer; Penpulimab: ant-PD-1 humanized mAb approved in China in August 2021 for Hodgkin’s lymphoma; Zimberelimab: anti-PD-1 human mAb approved in China in August 2021 for Hodgkin’s lymphoma; Prolgolimab (Forteca), anti-PD-1 mAb approved in Russia in 2020 for melanoma. |
ICI/Target | Vaccine | Disease | n | ICI-Vaccine Combination Strategy | Results | irAEs | References |
---|---|---|---|---|---|---|---|
Ipilimumab/CTLA-4 | T-VEC | Unresectable stage IIIB-IV melanoma | 198 | T-VEC was administered intratumorally at the first dose ≤4 mL × 106 pfu/mL, after 3 weeks at subsequent doses ≤4 mL × 108 pfu/mL every 2 weeks; four doses of ipilimumab 3 mg/kg were given intravenously every 3 weeks. | Combination therapy promoted a significantly higher objective therapeutic response rate than ipilimumab alone (39% vs. 18%). A decrease in visceral lesions was observed in 52% of patients treated with the combination and 23% of patients with ipilimumab alone. | Fatigue (59%), chills (53%), diarrhea (42%), pruritus (40%), rash (39%). The incidence rate of grade ≥3 irAEs was 45% in the combination and 35% with ipilimumab alone. | [62,63] |
Sipuleucel-T | mCRPC | 50 | All patients received 3 doses of intravenous Sipuleucel-T infusion once every 2 weeks. Patients received the first dose of ipilimumab either immediately following their last Sipuleucel-T infusion, or 3 weeks after their last vaccine infusion. Additional 3 doses of ipilimumab, 3 mg/kg was given to all patients every 3 weeks, for a total of 4 ipilimumab doses | The combination treatment induced CD4(+) and CD8(+) T lymphocytes activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4(+) circulating T lymphocytes, were associated with better clinical outcomes. However, combining Ipilimumab with Sipuleucel-T resulted in modest clinical activity. | The treatment was well tolerated. One patient underwent a grade 4 event (colitis with colonic perforation) and nine grade 3 events in seven patients. Interestingly, patients with an irAE were more likely to have a significant PSA response (any grade, p = 0.001, grade 3/4, p = 0.037). | [64] | |
PROSTVAC | mCRPC | 30 | PROSTVAC was administered subcutaneously at prime doses of 2 × 108 pfu/mL, with subsequent monthly doses of 1 × 109 pfu/mL. Intravenous ipilimumab was given (1, 3, 5, and 10 mg/kg) on the same day as the vaccine. | For patients receiving ipilimumab 10 mg/kg, overall survival was 37.2 months, very longer than historical controls of treatment with PROSTVAC or ipilimumab alone. | irAEs mostly occurred in patients treated with ipilimumab 10 mg/kg. Grades 1 to 2 injection-site reactions were the most common adverse events. Grades 3 to 4 irAEs, including rash, diarrhea, colitis, and endocrine events, were observed in 27% of patients, requiring replacement hormones or supportive measures | [65,66] | |
GVAX | mCRPC | 28 | All patients received GVAX intradermally. Priming dose of 5 × 108 cells with additional injections of 3 × 108 cells every 2 weeks for 24 weeks plus intravenous ipilimumab at doses of 0.3, 1, 3, and 5 mg/kg every 4 weeks. | 25% of patients showed >50% PSA reduction from baseline, and four patients obtained stable disease measured by bone scan. | Adverse events (>30%) were grades 1 to 2 injection-site reactions, fatigue, influenza-like symptoms, and rash. At, one patient receiving ipilimumab at 5 mg/kg, had grade 4 sarcoid alveolitis. Other irAEs related to ipilimumab included hypophysitis and hepatitis. Both responded to hormone replacement therapy. | [67,68] | |
Advanced pancreatic adenocarcinoma | 30 | Patients received either intravenous ipilimumab 10 mg/kg alone or intradermal GVAX at doses of 5 × 108 cells with subsequent ipilimumab 10 mg/kg. | The combination promoted prolonged disease stabilization, improved 1-year survival (27% vs. 7%), and a trend of favorable median overall survival (5.7 vs. 3.6 months; p = 0.072) compared with ipilimumab alone. CA19-9 responses were observed in 47% of patients that received combination therapy, whereas none in ipilimumab alone. | Grades 1 to 2 injection-site reactions, rash, fatigue, fever, and influenza-like illness. 20% of patients experienced grades 3 to 4 irAEs including rash, colitis, pneumonitis, and nephritis. All irAEs responded to steroids except for nephritis requiring hemodialysis | [69] | ||
Peptide Vaccine (gp100:209-217 and gp100:280-288 from gp100, a melanoma-associated antigen. | Progressive stage IV melanoma | 56 | Twenty-nine patients received 3 mg/kg Ipilimumab every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. The patients received concomitant vaccination with peptide vaccine. | Two patients had a complete response (at 30 and 31 months, respectively) while five patients achieved a partial response, for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites, and it was correlated with autoimmune reactions. | Of 14 patients with grade 3/4 autoimmune reactions, 36% experienced favorable clinical response. Only two favorable responses were observed in the 42 patients (5%) with no autoimmune reactions (p = 0.008). There were no significant differences in response rate or toxicity between the two-dose schedules. | [70] | |
TriMixDC-MEL | Pretreated advanced melanoma | 39 | TriMixDC-MEL was given subcutaneously and intravenously plus ipilimumab (10 mg/kg) every 3 weeks for four doses, followed by nivolumab (anti-PD1) maintenance every 3 months | The disease control rate was 51% at 6 months, and tumor objective response rate with the combination was 38%, which was higher than ipilimumab alone (10–15%). Tumor responses included eight complete and seven partial responses. | The most common adverse events (>30%) were injection-site reactions, influenza-like illness, dermatitis, and chills. 14 patients (36%) underwent grades 3 to 4 events, but most of them were reversible by using established treatment. | [71] | |
UV1 | Unresectable metastatic melanoma | 12 | Ipilimumab (3 mg/kg) was administered every 3 weeks for a total of 4 doses. Intradermal abdominal injections of UV1 vaccines (300 µg doses) were administered as before and between treatments of ipilimumab. Thereafter every fourth week up to 28 weeks, and at weeks 36 and 48. GM-CSF (sargramostim 75 µg) was injected at the same site 10–15 min prior to UV1. | Ten patients showed a Th1 immune response to UV1, occurring early and after a few vaccinations. Three patients obtained a partial response. One patient had a complete response. Overall survival was 50% at 5 years. | The adverse events observed were injection site reaction, pruritus, rash, nausea, diarrhea, and fatigue. | [72] | |
Atezolizumab/PDL-1 | Sipuleucel-T | mCRPC | Patients received either atezolizumab 1200 mg intravenously every 3 weeks for 2 doses followed by Sipuleucel-T three infusions every 2 weeks, or Sipuleucel-T every 2 weeks for a total of three infusions followed by atezolizumab as described (Phase Ib study) | The primary endpoint of this study was safety. There were no grade 5 adverse events attributed to the study drugs. Two patients underwent grade 4 toxicities, while eight grade 3 toxicities and four grade 3 toxicities were observed | None of the grade 3 or 4 adverse events were irAEs. | [73] | |
Pembrolizumab/PD1 | T-VEC | Unresectable stages IIIB-IV melanoma | 21 | Patients received T-VEC at an initial dose of 4 mL × 106 pfu/mL, followed 3 weeks later at a full dose of 4 mL × 108 pfu/mL every two weeks. Pembrolizumab 200 mg was injected intravenously coinciding with subsequent doses of T-VEC. | Combination therapy induced an objective response rate of 62%, almost twice as shown in the phase III study of pembrolizumab (34%) and T-VEC (26%). The complete response rate for per immune-related response criteria was 33%. An increase in lymphocyte infiltration, and IFN-γ gene expression was observed in patients who responded to combination therapy. | The most common adverse events observed were. fatigue (62%), chills (48%), fever (43%), rash (33%), and arthralgia (33%). One grade 1 reaction associated with the combination resulted in hospitalization, while other grades 3 to 4 AEs were due to pembrolizumab. In general, combination therapy did not increase the toxicity of monotherapy. | [74,75] |
Advanced squamous cell carcinoma of the head and neck | 36 | T-VEC was injected intralesionally at a first dose of 8 mL × 106 pfu/mL, and subsequent doses of 8 mL × 108 pfu/mL every 3 weeks. Intravenous pembrolizumab 200 mg was administered every 3 weeks | The objective response rate was 16.7% (six patients with five subjects PDL-1 positive), and the disease control rate was 38.9% (14 patients with 11 subjects PD-L1 positive). | The detected adverse events included pyrexia (36.1%), dyspnea (33.3%), and fatigue (25.0%). Grades 3 to 4 reactions were observed in 24 patients (66.7%). | [76,77] | ||
Nivolumab/PD1 | Peptide Vaccine (MART-1/NY-ESO-1/gp100 with Montanide ISA 51 VG) | Unresectable stages III to IV melanoma | 90 | In a phase I trial, patients were treated with an extended dose of nivolumab (1, 3, or 10 mg/kg) with or without vaccines. | For both ipilimumab-refractory and -naive subjects, the RECIST (Response Evaluation Criteria in Solid Tumors) response rates were 25%, and nivolumab-induced durable responses for up to 140 weeks | Fatigue and injection-site reaction were the most common adverse events, most of which were mild to moderate. Grade 3 irAEs (optic neuritis, fever, pneumonitis, and rash) were also observed and were successfully treated with prednisone as described previously for nivolumab monotherapy. | [78,79] |
Resected stages IIIC to IV melanoma | 33 | Patients were treated with an extended dose of nivolumab (1, 3, or 10 mg/kg) plus peptide vaccine every 2 weeks for 24 weeks, followed by nivolumab alone every 3 months for up to 2 years | The estimated median relapse-free survival (RFS) was 47.1 months compared with the historical median RFS (12–21 months). | Injection-site reaction, fatigue, rash, pruritus, nausea, and arthralgia were the most common reactions registered (>40%). Grade 3 reactions included hypokalemia, rash, enteritis, and colitis. All of them responded to systemic management of steroids and supportive care | [80,81,82] |
mAbs | Alternative Molecular ICIs | |
---|---|---|
Specificity | Highly specific but cross-reactivity can be observed | Highly specific but off-target interaction can be observed |
Diversity | mAbs can be obtained against a very wide range of target structures | |
Mechanisms of action | Specific blockade of the checkpoint’s interaction with their natural ligand on the cell surface | Blocking direct interaction between checkpoint’s interaction with their natural ligand, inhibiting transcription and translation of checkpoint; promoting checkpoint degradation |
Purity | High purity | High purity |
Molecular weight | High molecular weight (~150 kDa) | Low molecular weight (~6 to10 kDa) |
Structure | Glycoproteins with complex structure | Short, single-stranded DNA or RNA with chemical modifications, short linear peptides, cyclopeptides, or small synthetic molecules |
Thermal Stability | Low stability. Cold chain through the storage, handling, and transportation is necessary | Highly stable. Lyophilization and freezing do not modify their biological activity |
Bioavailability | No oral bioavailability and inability to penetrate the cells. The Fc domain of IgG antibody can interact with diverse cell receptors which hinder reaching the targets | They can penetrate the cells and act on intracellular targets |
Secreted target | Secreted targets (e.g from tumor cells), can interrupt antibody-mediated immune reactions in the tumor microenvironment. | Their targets are mainly intracellular |
Immunogenicity | Highly immunogenic by xenogeneic differences, e.g., between mice and humans | They are not properly immunogenic |
Toxicity | Different grades of toxicity have been described | Relatively low toxicity associated with off-target effects |
Development and Manufacturing | Immortal hybridomas cell lines produce unlimited quantities of antibodies, but industrial production is technologically complex | They are obtained synthetically. The use of vehicles can add complexity to the manufacturing process |
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Batista-Duharte, A.; Hassouneh, F.; Alvarez-Heredia, P.; Pera, A.; Solana, R. Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches. Pharmaceutics 2022, 14, 1721. https://doi.org/10.3390/pharmaceutics14081721
Batista-Duharte A, Hassouneh F, Alvarez-Heredia P, Pera A, Solana R. Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches. Pharmaceutics. 2022; 14(8):1721. https://doi.org/10.3390/pharmaceutics14081721
Chicago/Turabian StyleBatista-Duharte, Alexander, Fakhri Hassouneh, Pablo Alvarez-Heredia, Alejandra Pera, and Rafael Solana. 2022. "Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches" Pharmaceutics 14, no. 8: 1721. https://doi.org/10.3390/pharmaceutics14081721
APA StyleBatista-Duharte, A., Hassouneh, F., Alvarez-Heredia, P., Pera, A., & Solana, R. (2022). Immune Checkpoint Inhibitors for Vaccine Improvements: Current Status and New Approaches. Pharmaceutics, 14(8), 1721. https://doi.org/10.3390/pharmaceutics14081721