Immune Checkpoint to Watch: ICOS

Julio C. Chavez, MD, MS

Immune receptor inducible co-stimulator (ICOS), essential to the regulation of T cells, is playing a trending role in innovative cancer immunotherapy research; early data of its potential advantages suggests continued investigation. Expressed by activated cytotoxic T cells and regulatory T cells, the ICOS molecule could potentially serve as an indicator of immune response to therapy and is being evaluated across multiple treatment strategies. Furthermore, the dual effect of the ICOS/ICOS-L (inducible co-stimulator ligand) axis may provide a potential opportunity to have said pathway targeted by both agonist and antagonist antibodies.¹

As a member of the CD28 superfamily, the ICOS pathway begins via ligation expressed on B-cells and phagocytes. A downstream pathway is then triggered, regulating both T-cell proliferation and secretion of cytokines. On activated CD4 and CD8 T-cell subsets ICOS is upregulated, possibly representing a sensitive and strategic quantifier in targeting responses for select diagnoses of patients with cancer.²

Oncologist Julio C. Chavez, MD, MS, is the current principal investigator of multiple clinical trials related to the use of immunotherapy and targeted agents. Chavez, an associate member in the Lymphoma Section of the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, discussed the use of this emerging immunologic trend in the oncology setting, stating, “The ICOS is a novel immune checkpoint that is associated with T-cell development, specifically T follicular helper [Tfh] cells. It is thought that Tfh cells are important in oncogenesis, particularly in T-cell lymphomas; specifically in angioimmunoblastic T-cell lymphoma [AITL] and peripheral T-cell lymphomas [PTCL] follicular type.”

Developing modern strategies to predict and accurately monitor treatment response remains an important piece of the clinical management puzzle. While immunotherapy holds innovative potential in the oncology sector, current therapies offered may only benefit a small fraction of patients. And, though more conventional imaging modalities (such as CT and MRI) remain current standards of assessment, certain limitations of these exams exist along with potential lag time between imaging and response assessment. Hence, an increased interest in comprehensive research efforts to identify a helpful marker, specifically one that accurately reflects the patient’s response to immunotherapy. PD-L1 immunohistochemistry and T-cell repertoire sequencing have been utilized as biomarkers, predicting response to immunotherapy; however, these novel approaches do still require invasive site biopsies.²

Results from Early Studies of ICOS Agents

Several clinical trials utilizing the ICOS checkpoint in treating both solid and liquid tumor cancers have already been conducted and early responses have been mixed for monotherapy agents. However, investigators still believe in the potential of this checkpoint as part of combination regimens.

NCI-9930 is a phase 1 study (NCT02520791) of the ICOS blockade by MEDI-570, an ICOS-directed human afucosylatedIgG1 kappa monoclonal antagonistic antibody, in patients with relapsed/refractory malignant T-cell lymphomas. A total of 5 dose levels were studied, with 12 cycles of intravenous administration of MEDI-570 given every 3 weeks. Promising clinical results were documented in certain subtypes of angioimmunoblastic T-cell lymphomas (AITL)—there were 4 partial responses and 7 cases of stable disease, and the agent also resulted in reductions in targeted ICOS-positive T lymphocytes. Also, MEDI-570 was found to be well tolerated among recipient patients.³

Chavez commented on the MEDI-570 trial, saying, “This was a dose escalation/expansion phase 1 study that just completed enrollment. We presented the preliminary efficacy at the American Society of Hematology [ASH] meeting in December 2020. Patients enrolled in the study were heavily pretreated, including prior autologous transplantation. MEDI-570 proved to be safe. It was particularly efficacious in AITL with 4 out 12 partial responses, which were durable. Given its safety, I believe that MEDI-570 can be combined with other agents known to have activity in T-cell lymphomas, including chemotherapy.”

Chavez was asked to express his view of whether or not ICOS research trials should continue along with potential corresponding value and benefits within the oncology sector. He stated, “ICOS is a novel checkpoint that targets T cells [that] are involved in oncogenesis, particularly lymphomagenesis. Given the preliminary safety and efficacy of MEDI-570, it has the potential to be safely combined with other agents.” Chavez added, “Therefore, [utilizing ICOS offers] potential improvements in the treatment of T-cell lymphomas, which usually have a poor prognosis.”

Feladilimab (formerly GSK3359609), an ICOS receptor agonist non–T-cell depleting monoclonal antibody, was first studied in an open-label, multicenter, phase 1 trial (INDUCE-1; NCT02723955) in those with advanced solid tumors of varied histology. Safety, dose escalation, and expansion phases were explored with feladilimab as both a monotherapy and in combination with varied treatment options. Several study arms currently aim to investigate the use of feladilimab along with other therapies, including pembrolizumab (Keytruda) and a multitude of chemotherapies at standard-of-care doses and schedules (docetaxel, pemetrexed, paclitaxel, gemcitabine, or fluorouracil [5-FU]), in addition to dostarlimab (Jemperli), cobolimab, or bintrafusp alfa. The study is currently recruiting, with an estimated study completion date of December 2024.

Among 10 evaluable patients treated with feladilimab, 5-FU, and platinum chemotherapy with or without pembrolizumab from the trial, 2 patients had partial response and 6 had stable disease. In those not treated with pembrolizumab, 9 of 10 patients experienced at least 1 adverse event (AE). Three serious events were reported, 2 of which were potentially related to the study treatment. With the addition of pembrolizumab, 94.7% of patients experienced at least 1 AE, including 15 serious events, 11 of which were potentially treatment related. No grade 5 events were observed in either cohort.⁴

In the urothelial carcinoma expansion cohorts, in patients who previously received a PD-1/PD-L1 inhibitor, feladilimab monotherapy induced an overall response rate (ORR) of 7%, a disease control rate for at least 18 weeks of 21%, and a duration of response of 6.1 months. The median overall survival (OS) was 14.5 months and 77% of patients were still alive at 6 months. With feladilimab in combination with pembrolizumab in patients naïve to PD-1/PD-L1 inhibition, the ORR was 22%, the disease control rate for at least 18 weeks was 44%, and the median duration of response was 8.3 months. The median OS was 10.7 months and 64% of patients were still alive at 6 months. Grade 3 or higher treatment-related AEs were reported in 9% of patients in the combination arm but none were observed in the monotherapy arm.⁵

In the INDUCE-3 trial (NCT04128696), patients with PD-L1–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) were enrolled in the double-blinded phase 2/3 study in which feladilimab was given in combination with either pembrolizumab or placebo. In the INDUCE-4 study (NCT04428333), feladilimab was evaluated in a comparison of 2 randomized combination strategies: feladilimab with pembrolizumab and 5-FU plus platinum-based chemotherapy or placebo with pembrolizumab and 5-FU. Similar to the INDUCE-3 trial, participants had recurrent or metastatic HNSCC. However, as of April 2021, GlaxoSmithKline plc (GSK) has halted enrollment in both the INDUCE-3 and the INDUCE-4 phase 2 studies, following a recommendation by the Independent Data Monitoring Committee.⁶ Specific details surrounding data and reasons for the stoppages were not made public.

Vopratelimab (formerly JTX-2011) trials began in late 2016 and it was the first agonist anti-ICOS antibody to be studied; however, initial data from the phase 1/2 trial (ICONIC; NCT02904226) were unsatisfactory with only 1 of 67 patients showing a partial response from monotherapy and 8 of 106 patients responding on combination vopratelimab and nivolumab (Opdivo).⁷

An analysis of the trial, though, showed that there were higher response rates and survival rates among patients with ICOShigh CD4 T-cell emergence who were also more likely to have a higher RNA signature cutoff of immune cell infiltration and PD-L1 expression. Among patients with this higher RNA signature (n = 11), the ORR was 27.3% and the disease control rate was 54.5%. The median progression-free survival was 3.1 months and the rate at 6 months was 36.4%. The median OS was not reached. In patients with a lower RNA signature (n = 23), the ORR was 13.0% and the disease control rate was 43.5%. The median progression-free survival was 2.2 months and the rate at 6 months was 20.1%. The median OS was 20 months.⁸

In 2019, Jounce Therapeutics began an open-label phase 2 trial (EMERGE; NCT03989362), in which a combination of vopratelimab and ipilimumab (Yervoy; a CTLA-4 inhibitor) was evaluated; subjects had a diagnosis of either advanced and/ or refractory non–small cell lung cancer (NSCLC) or urothelial cancer and were exposed to prior PD-1/PD-L1 inhibition.

Vopratelimab is an agonist monoclonal antibody thought to generate an anti-tumor response by binding to ICOS. This refined approach, combining an anti-ICOS with an anti–CTLA-4 treatment has the potential to increase overall efficiency.⁷

However, the NSCLC group was not projected to meet the criteria for continued enrollment into the cohort. Thus, the developers decided the trial should not be expanded to patients with urothelial carcinoma. Instead, the phase 2 SELECT trial (NCT04549025) is enrolling and exploring the use of an investigational PD-1 inhibitor JTX-4014 with or without added vopratelimab in biomarker-selected patients with metastatic NSCLC following 1 prior platinum-containing treatment regimen who are naïve to PD-1/PD-L1 inhibition.⁹

Safety, efficacy, and tolerability of KY1044 (human anti-ICOS antibody) as a monotherapy and in combination with atezolizumab (Tecentriq) is being tested in a phase 1/2 trial (NCT03829501), aimed at those diagnosed with advanced malignancies. Eligible patients included those who were ineligible for other therapies or for patients who had no beneficial treatments available to them.¹⁰

Preliminary results from the trial showed that 5 patients achieved a response to the combination regimen, which included a complete response in 1 patient with triple-negative breast cancer and partial responses in 4 patients.¹¹

In order to improve clinical cancer management, harnessing potential immunotherapy strategies that increase opportunities for monitoring and prediction are essential. Therapies utilizing antibodies that target immune checkpoints continue to be part of the novel shift toward immunotherapy in oncologic care. Immune checkpoint inhibitors can exhibit a response for those with certain malignancies, such as NSCLC, renal, bladder, and head and neck cancers. Patients with resistance to immune checkpoint inhibitors, however, may benefit from newly combined therapeutic approaches.12 Thus, continued research and strategy involving the possible use of therapeutic antibodies as both a monotherapy and as a part of innovative combination therapies is of interest and of potential future benefit to the oncologic community. Although an increased understanding of whether inhibition of expression or blockage would provide the most favorable therapeutic outcomes for select cases, it remains clear that utilizing the ICOS/ICOS-L signal pathway only has the potential to improve the future of oncology care.

“I believe that the targeting of ICOS represents a novel immunotherapeutic approach,” Chavez said. “There should be a continuous effort to further explore this pathway.”

_References:

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_{2. Xaio Z, Mayer A, Nobashi TW, Gambhir SS. ICOS is an indicator of T-cell-meditated response to cancer immunotherapy. Cancer Res. 2020;80(14):3023-3032. doi:10.1158/0008-5472.CAN-19-3265}

_{3. Chavez JC, Foss FM, William BM, et al. A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930). Blood. 2020;136(suppl 1):5-6. doi:10.1182/blood-2020-136465}

_{4. Massarelli E, Balmanoukian AS, Vieito M, et al. INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. J Clin Oncol. 2020;38(suppl 15):6544. doi:10.1200/JCO.2020.38.15_suppl.6544}

_{5. Balar AV, Moreno V, Angevin E, et al. Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs). J Clin Oncol. 2021;39(suppl 15):4519. doi:10.1200/JCO.2021.39.15_suppl.4519=}

_{6. GSK Provides Update on Feladilimab, an Investigational Inducible T Cell Co-Stimulatory (ICOS) Agonist. News release. GlaxoSmithKline. April 14, 2021. Accessed August 10, 2021. https://bit.ly/2Y5co9C}

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_{8. Yap TA, Gainor JF, Burris HA, et al. Association of an RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial. J Clin Oncol. 2020;38(suppl 5):14.}

_{9. Jounce Therapeutics Announces Update on Vopratelimab Program. News release. Jounce Therapeutics, Inc. November 2, 2020. Accessed August 10, 2021. https://bit.ly/3DIvu5S}

_{10. Marinelli O, Nabissi M, Morelli MB, Torquati L, Amantini C, and Santoni G. (2018). ICOS-L as a Potential Therapeutic Target for Cancer Immunotherapy. Curr Protein Pept Sci. 2018;19(11):1107-1113. doi:10.2174/1389203719666180608093913}

_{11. Patel MR, Naing A, Burris HA, et al. A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies. J Clin Oncol. 2021;39(suppl 15):2624. doi:10.1200/JCO.2021.39.15_suppl.2624}

_{12. Sainson R, Thotakura AK, Kosmac M, et al. An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression. Cancer Immunol Res. 2020;8(12):1568-1582. doi:10.1158/2326-6066.CIR-20-0034}