Over the past decade, cancer regimens featuring CTLA-4 inhibitor monotherapy have largely been replaced by combination regimens pairing these agents with anti–PD-1/ PD-L1 antibodies.
Investigators developing newer 4 (CTLA-4) monoclonal antibodies will build upon the foundation and legacy of early immune checkpoint inhibitors (ICIs) while improving the treatment of patients with cancer with greater efficacy and reduced toxicity.1
CTLA-4 was the first immune checkpoint to be targeted with an ICI, with the fully human immunoglobulin G1 (IgG1) anti–CTLA-4 monoclonal antibody ipilimumab (Yervoy) approved by the FDA in 2011.1 Early exploration of CTLA-4 launched research into ICIs, which has produced such significant clinical results that James P. Allison, PhD, was awarded the Nobel Prize in Physiology or Medicine in 2018.2
CTLA-4 is a CD28 homologue that binds to CD80/CD86 (B7 ligands) with high avidity and affinity to inhibit T-cell function.1,3 It is expressed on the surface of activated CD4-positive (+) and CD8+ T cells. CTLA-4 is also expressed constitutively on regulatory T lymphocytes (Tregs), which helps support their suppressive function.
CTLA-4 is understood to mediate immuno-suppression by blocking the T-lymphocyte response, reducing the proliferation of T lymphocytes and increasing the activity of Tregs.4-6
By blocking this checkpoint using anti– CTLA-4 antibodies, investigators have been able to release the brakes on the immune system, thus increasing the function of professor of medicine and leader of the Melano-effector CD4+ and CD8+ T cells, as well as depleting intratumoral Tregs.
Over the past decade, cancer regimens featuring CTLA-4 inhibitor monotherapy have largely been replaced by combination regimens pairing these agents with anti–PD-1/ PD-L1 antibodies. Anti–CTLA-4 antibodies have been shown to enhance the efficacy of PD-1/PD-L1 blockade in various solid tumors, with additive or even synergistic effects. However, the mechanism underlying this is not completely understood.
Ipilimumab is an anti–CTLA-4 monoclonal antibody that was developed by Bristol Mers Squibb. It has a half-life of 12 to 14 days.
The agent was first approved at 3 mg/kg for use in patients with unresectable or metastatic melanoma, representing the first therapy, at that time, to demonstrate a significant improvement in overall survival (OS) in patients.7 In a phase 3 study (NCT00094653), patients treated with ipilimumab monotherapy had a median OS of 10.1 months (95% CI, 8.0- 13.8) and a 1-year OS rate of 45.6%.8
Currently, ipilimumab has 9 indications in melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non–small cell lung cancer (NSCLC), and malignant pleural mesothelioma. With the exception of 2 of the melanoma indications, all the indications for ipilimumab are in combination with nivolumab (Opdivo), a PD-1 inhibitor.9
“The major issue of anti–CTLA-4 is it induces these autoimmune adverse events.... That’s a manageable problem because we know how to manage toxicity and most of these patients can manage it successfully,” said Mario Sznol, MD professor of Medicine and leader of Melanoma Program at Yale Cancer Center, in an interview with Targeted Therapies in Oncology. However, he added that we do not yet know the optimal dose of ipilimumab, either as a single agent or in combination with other drugs.
A dose-ranging phase 2 study (NCT00289640) of ipilimumab in patients with pretreated advanced melanoma showed that higher doses of the CTLA-4 inhibitor led to greater response rates, but with higher rates of immune-related adverse events (irAEs). At 10 mg/kg, the overall response rate was 11.1% (95% CI, 4.9%-20.7%) compared with 4.2% (95% CI, 0.9%-11.7%) at 3 mg/kg and 0% (95% CI, 0.0%-4.9%) at 0.3 mg/kg (P = .0015). IrAEs were reported in 70.4% of patients treated with the 10-mg/kg dose, in 64.8% with the 3-mg/kg dose, and in 26.4% with the 0.3-mg/kg dose.10
These irAEs have become more manageable with supportive measures, including the use of steroids, and an increased understanding of autoimmune toxicities.11 However, investigators continue to explore whether different dosing schedules could reduce the incidence of these events without reducing efficacy.12
For example, in the phase 3b/4 CheckMate 511 trial (NCT02714218), 2 dosing regimens of nivolumab and ipilimumab were compared for patients with advanced melanoma: nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3+IPI1) vs nivolumab 1 mg/kg and ipilimumab 3 mg/kg (NIVO1+IPI3). The objective response rate (ORR) with NIVO3+ IPI1 was 45.6% (95% CI, 38.1%-53.1%) compared with 50.6% (95% CI, 43.0%-58.1%) with NIVO1+IPI3 (P = .35). The median progression-free survival (PFS) was 9.9 months and 8.9 months with NIVO3+IPI1 and NIVO1+IPI3, respectively, and the median OS was not yet reached in either group. The rate of grade 3 to 5 treatment-related AEs (TRAEs) was 33.9% (95% CI, 27.0%-41.3%) with NIVO3+ IPI1 as compared with 48.3% (95% CI, 40.8%- 55.9%) with NIVO1+IPI3 (P = .006).13
Next Wave of CTLA-4 Blockade
“A major question, from the perspective of therapeutics development, is whether the risk-benefit ratio and overall clinical activity of CTLA-4 inhibitors can be substantially improved, either by modifying dose and schedule, altering the biological activities or site of effects, or considering other types of combinations,” Sznol wrote in an editorial in Annals of Oncology.14
Tremelimumab is a fully human IgG2 anti–CTLA-4 monoclonal antibody first developed by Pfizer that has a half-life of 22.1 days.15 The rights were later acquired by AstraZeneca. Both tremelimumab and ipilimumab bind to the same region on CTLA-4, but these agents have different antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. Structurally, both agents use similar VH framework regions but very different VL regions.16
This anti–CTLA-4 antibody has yet to be FDA approved despite several preclinical and clinical studies. Trials with the agent have produced mixed results across clinical settings. In the phase 3 MYSTIC trial (NCT02453282), the combination of tremelimumab with the PD-L1 inhibitor durvalumab (Imfinzi) did not meet the primary end point of improved PFS compared with platinum-based chemotherapy for patients with previously untreated metastatic NSCLC.17 Later, the POSE- IDON trial (NCT03164616) became the first phase 3 study to show an OS benefit with this CTLA-4 inhibitor; tremelimumab combined with durvalumab and chemotherapy was superior to chemotherapy alone in patients with previously untreated, metastatic NSCLC.18
Quavonlimab (MK-1308) is a new IgG1 anti– CTLA-4 monoclonal antibody in development by Merck. Sznol suggested that quavonlimab has a higher binding affinity for CTLA-4 than ipilimumab.14
A phase 1/2 trial (NCT03179436) examined the combination of quavonlimab and pembrolizumab (Keytruda) in patients with advanced solid tumors. The goal of the dose-escalation phase was to determine the recommended phase 2 dose for quavonlimab when given in combination with pembrolizumab; then, the dose-confirmation portion of the study evaluated this dose in patients with previously untreated stage IIIB/IV NSCLC. In dose escalation, patients received a flat dose of quavonlimab at 25 mg, 75 mg, or 200 mg, followed by 4 cycles of quavonlimab at the same dose combined with pembrolizumab.19
The maximum tolerated dose of quavonlimab was not reached. The recommended phase 2 dose was determined to be 25 mg given every 6 weeks, as this led to the lowest toxicity without reducing efficacy.
Among patients with treatment-naïve NSCLC, the ORR was 35.1%. The median PFS was 6.1 months, and the median OS was 16.5 months. Fifty-eight percent of responding patients had responses lasting at least 12 months as of data cutoff.
Sznol noted that response rates and the rate of grade 3 or higher AEs for the combination were similar to those of ipilimumab and nivolumab.14
Quavonlimab is being explored further in clinical trials in other settings, including in a phase 3 trial in combination with pembrolizumab compared with other combinations in patients with advanced clear cell renal cell carcinoma (NCT04736706).
Zalifrelimab (AGEN1884) is a fully humanized IgG1 anti–CTLA-4 monoclonal antibody in development by Agenus.20
The agent was investigated in combination with a novel PD-1 inhibitor, balstilimab, in patients with advanced cervical cancer in a phase 1/2 trial (NCT03495882). Patients received zalifrelimab at a dose of 1 mg/kg once every 6 weeks plus 3 mg/kg balstilimab once every 2 weeks for up to 24 months.21
The ORR was 25.6% (95% CI, 18.8%-33.9%), and the disease control rate (DCR) was 52% (95% CI, 43.3%-60.6%). The median duration of response had not been reached at the time of data cutoff.
This CTLA-4 inhibitor is being studied further in phase 2 studies as a monotherapy in patients with solid tumors (NCT03104699) and in combination with balstilimab for patients with recurrent and/or metastatic cervical cancer (NCT03894215).
GIGA-564 is an anti–CTLA-4 antibody in development by GigaGen Inc that has a novel mechanism of action: instead of blocking the CTLA-4–B7 ligand interaction, GIGA-564 depletes intratumoral Tregs via enhanced Fc receptor activity. The agent binds to a CTLA- 4 epitope very close to that of ipilimumab; nonetheless, it exhibits strongly reduced checkpoint inhibition. Depite the weaker inhibition, low doses of GIGA-564 showed superior antitumor activity and reduced toxicity compared with ipilimumab in murine models.22
This agent has yet to be studied in clinical settings, but if validated, it could prompt a new approach to designing CTLA-4 agents.
CBT-509 is a novel IgG1 humanized anti– CTLA-4 monoclonal antibody that binds to a distinct epitope of CTLA-4 vs ipilimumab. This agent has demonstrated more than 4-fold higher binding affinity to CTLA-4 vs ipilimumab.23
In preclinical research, CBT-509 showed morepotenthumanT-cellactivationinvitroand greater efficacy in killing tumor cells in vivo compared with ipilimumab. In a murine colorectal cancer model, CBT-509 achieved tumor eradication in 7 of 8 mice compared with 4 of 8 mice treated with ipilimumab.
AGEN1181 is a next-generation anti–CTLA-4 monoclonal antibody in development by Agenus with enhanced Fcγ receptor–dependent functionality, which promotes enhanced T-cell priming and intratumoral Treg depletion. Additionally, AGEN1181 binds to both high- and low-affinity versions of FcγRIIIA, which expands the therapeutic potential of the agent while avoiding complement-mediated toxicity. AGEN1181 has a half-life of 13.4 days.24,25
In a phase 1/2 trial (NCT03860272), AGEN1181 was explored as monotherapy and in combination with balstilimab in patients with advanced solid tumors. The DCR was 44.8% with AGEN1181 monotherapy, which increased to 64.4% when the agent was combined with balstilimab. Responses were observed across 9 treatment-resistant, poorly immunogenic tumor types in heavily pretreated patients. In patients with microsatellite-stable colorectal cancer (n = 20), the DCR was 70% and included 4 partial responses.25
The maximum tolerated dose was not reached for either the monotherapy or the combination. Grade 3 to 5 TRAEs were reported in 20.7% of patients. Discontinuation due to TRAEs was observed in 16% of patients, primarily due to diarrhea/colitis. No immune- related hypophysitis, pneumonitis, or high- grade hepatitis was reported in the study.
Phase 2 and 3 potentially registrational studies are being initiated to evaluate for AGEN1181 both as monotherapy and in combination with balstilimab for patients with microsatellite-stable colorectal cancer and gynecologic cancers.
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2. The Nobel Prize in Physiology or Medicine 2018. News release. The Nobel Prize. October 1, 2018. Accessed March 1, 2022. https://bit.ly/3tpSG4n
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4. Leung HT, Bradshaw J, Cleaveland JS, Linsley PS. Cytotoxic T Lymphocyte-associated Molecule-4, a High Avidity Receptor for CD80 and CD86, Contains an Intracellular Localization Motif in Its Cytoplasmic Tail. J Biol Chem. 1995;270(42):25107-25114. doi:10.1074/jbc.270.42.25107
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8. FDA Approves YERVOY™ (ipilimumab) for the Treatment of Patients with Newly Diagnosed or Previously-Treated Unresectable or Metastatic Melanoma, the Deadliest Form of Skin Cancer. News release; Bristol Myers Squibb. March 25, 2011. Accessed March 1, 2022. https://bit.ly/3tmbL7K
9. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med.2010;363(8):711-723. doi:10.1056/NEJMoa1003466
10. Yervoy (ipilimumab). Prescribing information. 2022. Accessed March 1, 2022. https://bit.ly/3IBkglxLetendre P, Monga V, Milhem M, Zakharia Y. Ipilimumab: from preclinical development to future clinical perspectives in melanoma. Future Oncol.2017;13(7):625-636. doi:10.2217/fon-2016-0385
11. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol.2010;11(2):155-164. doi:10.1016/S1470-2045(09)70334-1
12. Weber JS, Kähler KC, Hauschild A. Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab. J Clin Oncol.2012;30(21):2691-2697. doi:10.1200/JCO.2012.41.6750
13. Lebbé C, Meyer N, Mortier L, et al. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol.2019;37(11):867-875. doi:10.1200/JCO.18.01998
14. Sznol M, Melero I. Revisiting anti-CTLA-4 antibodies in combination with PD-1 blockade for cancer immunotherapy. Ann Oncol. 2021;32(3):295-297. doi:10.1016/j.annonc.2020.11.018
15. Tarhini AA. Tremelimumab: a review of development to date in solid tumors. Immunotherapy.2013;5(3):215-229. doi:10.2217/imt.13.9
16. He M, Chai Y, Qi J, et al. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget. 2017;8(40):67129-67139. doi:10.18632/oncotarget.18004
17. AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer. News release. AstraZeneca. July 27, 2017. Accessed March 1, 2022. https://bit.ly/3vsnOmF
18. Imfinzi and tremelimumab with chemotherapy demonstrated overall survival benefit in POSEIDON trial for 1st-line Stage IV non-small cell lung cancer. News release. AstraZeneca. May 7, 2021. Accessed March 1, 2022. https://bit.ly/3hxzOuU
19. Perets R, Bar J, Rasco DW, et al. Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer. Ann Oncol.2021;32(3):395-403. doi:10.1016/j.annonc.2020.11.0
20. Gombos RB, Gonzalez A, Manrique M, et al. Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody. PLoS One. 2018;13(4):e0191926. doi:10.1371/journal.pone.0191926
21. O’Malley DM, Neffa M, Monk BJ, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase II study. J Clin Oncol. 2022;40(7):762-771.doi:10.1200/JCO.21.02067
22. Stone EL, Carter KP, Wagner EK, et al. Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy. bioRxiv. Posted online July 12, 2021. doi:10.1101/2021.07.12.452090
23. Shi Q, Liu Y, Yang L, MaH, Ma W, Sun Z. A novel humanized anti-CTLA-4 antibody compared to ipilimumab in preclinical studies.J Clin Oncol. 2019;37(suppl 8):32. doi:10.1200/JCO.2019.37.8_suppl.32
24. O’Day S, Ramamurthy C, Bullock A, et al. AGEN1181, a Clinical Stage Fc-engineered anti-CTLA-4 Antibody With Improved Therapeutic Potential for the Treatment of Patients With Advanced Malignancies. J Clin Oncol. 2020;38(suppl 15):TPS3157. doi:10.1200/JCO.2020.38.15_suppl.TPS3157
25. El-Khoueiry AB, Bullock AJ, Tsimberidou AM, et al. AGEN1181,an Fc-enhanced anti-CTLA-4 antibody, alone and in combination with balstilimab (anti-PD-1) in patients with advanced solid tumors: Phase I results. Presented at: 2021 Society for Immunotherapy of Cancer Annual Meeting; November 10-14, 2021; virtual. Abstract 479.