Approval Of Immune Checkpoint Inhibitors Research Articles

Programmed Cell Death-Ligand 1 Expression and Clinical Outcomes Among Patients with Resected, Early-Stage Non-Small Cell Lung Cancer: A Real-World Study

Treatment options for non-small cell lung cancer (NSCLC) are evolving, given recent and expected approvals of immune checkpoint inhibitors (ICIs) targeting programmed cell death-(ligand) 1 (PD-1/PD-L1). We retrospectively evaluated outcomes among patients with resected stage IB-IIIA NSCLC tumors expressing PD-L1 using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2016–2019). Key outcomes included PD-L1 expression rate and treatment patterns, recurrence, and median overall (mOS) and disease-free survival (mDFS) among PD-L1+ patients. Among 539 PD-L1–tested patients, 317 (58.8%) were PD-L1+ (≥1%). At diagnosis, 35.3%, 39.8%, and 24.9% of PD-L1+ patients had stage IB, II, or IIIA disease. Forty-one percent had received adjuvant therapy. At 22.6 months (median follow-up), first disease recurrence had occurred in 31.9% of patients, primarily at metastatic sites. After first metastatic recurrence, ICI regimens were the most common first systemic therapy (29.8%). mOS was not reached; mDFS was 40.0 months. At four years, DFS probability was 44%. Four-year OS and DFS rates were generally similar when stratified by PD-L1 expression (1–49% vs. ≥50%). These findings underscore the generally poor outcomes experienced by patients with early-stage, resected, PD-L1+ NSCLC after treatment with available adjuvant therapies, and provide context to recent and emerging trials of new treatment options.

Immunotherapy as a new perspective for the therapy of esophageal cancer

Abstract The therapeutic landscape in nearly every therapeutic line in advanced/metastatic patients with squamous cell carcinoma (SCC) and esophagogastric adenocarcinoma (EGC) is enriched by recent approvals of immune checkpoint inhibitors (ICIs). In curative intended therapy, patients without pathological residual disease of SCC or GEJ (esophagogastric junction) cancer after preoperative chemoradiation and complete resection have access to adjuvant immunotherapy (independent of PD-L1 (programmed cell death protein 1) status, nivolumab, CHECKMATE 577). For metastatic SCC in the first-line, nivolumab combined with chemotherapy or with ipilimumab (TPS (tumor proportion score) ≥1 %, SCC, CHECKMATE 648) are approved, as well as second-line nivolumab alone regardless of PD-L1 status (ATTRACTION 03). For both, locally advanced or metastatic SCC and EGC, chemotherapy with pembrolizumab is available for patients with CPS (combined positive score) ≥10 (KEYNOTE 590) and for adenocarcinoma with nivolumab (CPS ≥5, CHECKMATE 649). Recent added approvals are chemotherapy with pembrolizumab in CPS ≥1 patients (KEYNOTE 859) and the addition of trastuzumab for personalized therapy in HER-2 positive/CPS ≥1 gastric and GEJ patients (KEYNOTE 811).

Lost at SCLC: a review of potential platinum sensitizers.

The expression "lost at sea" means to be confused or perplexed. By extension, lost at SCLC references the current confusion about how to circumvent the chemoresistance, particularly platinum resistance, which so plagues the treatment of extensive-stage small cell lung cancer (ES-SCLC) that in 2012 the US National Cancer Institute (NCI) designated it a "recalcitrant cancer." Over a decade later, despite the approval of immune checkpoint inhibitors and the conditional approval of lurbinectedin, the prognosis for ES-SCLC, and especially platinum-resistant ES-SCLC, has scarcely improved. The focus of this review, which briefly summarizes current treatment options for ES-SCLC, is on five clinical-stage therapies with the potential to successfully reverse the platinum resistance that is perhaps the biggest obstacle to better clinical outcomes.

TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3

PurposeImmune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC.MethodsWe employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers).ResultsWe did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3.ConclusionOur findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.

Immunomodulatory effects of antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma models: Impact on following anti-PD-1 treatments

The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab.To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet.Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.

Clinical Outcomes of Immune Checkpoint Inhibitors in Unique Cohorts Underrepresented in Clinical Trials.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours.

Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and gastrointestinal cancers, many patients still show limited response. US Food and Drug Administration (FDA)-approved biomarkers include programmed cell death 1 ligand 1 (PDL1) expression, microsatellite status (that is, microsatellite instability-high (MSI-H)) and tumour mutational burden (TMB), but these have limited utility and/or lack standardized testing approaches for pan-cancer applications. Tissue-based analytes (such as tumour gene signatures, tumour antigen presentation or tumour microenvironment profiles) show a correlation with immune response, but equally, these demonstrate limited efficacy, as they represent a single time point and a single spatial assessment. Patient heterogeneity as well as inter- and intra-tumoural differences across different tissue sites and time points represent substantial challenges for static biomarkers. However, dynamic biomarkers such as longitudinal biopsies or novel, less-invasive markers such as blood-based biomarkers, radiomics and the gut microbiome show increasing potential for the dynamic identification of ICI response, and patient-tailored predictors identified through neoadjuvant trials or novel ex vivo tumour models can help to personalize treatment. In this Perspective, we critically assess the multiple new static, dynamic and patient-specific biomarkers, highlight the newest consortia and trial efforts, and provide recommendations for future clinical trials to make meaningful steps forwards in the field.

Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.

e14693 Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. [Table: see text]

QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564.

TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy &gt; 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .

Renal Cell Carcinoma of Variant Histology: New Biologic Understanding Leads to Therapeutic Advances.

Renal cell carcinoma (RCC) is one of the 10 most commonly diagnosed solid tumors. Most RCCs are histologically defined as clear cell, comprising approximately 75% of diagnoses. However, the remaining RCC cases are composed of a heterogeneous combination of diverse histopathologic subtypes, each with unique pathogeneses and clinical features. Although the therapeutic approach to both localized and metastatic RCCs has dramatically changed, first with the advent of antiangiogenic targeted therapies and more recently with the approval of immune checkpoint inhibitor (ICI)-based combinations, these advances have primarily benefited the clear cell RCC patient population. As such, there remains critical gaps in the optimization of treatment regimens for patients with non-clear cell, or variant, RCC histologies. Herein, we detail recent advances in understanding the biology of RCC with variant histology and how such findings have guided novel clinical studies investigating precision oncology approaches for these rare subtypes. Among the most common variant histology RCCs are papillary RCC, comprising approximately 15%-20% of all diagnoses. Although a histopathologically diverse subset of tumors, papillary RCC is canonically associated with amplification of the MET protooncogene; recently completed and ongoing trials have investigated MET-directed therapies for this patient population. Finally, we discuss the unique biology of RCC with sarcomatoid dedifferentiation and the recent clinical findings detailing its paradoxical sensitivity to ICIs.

Current Progress in Vaccines against Merkel Cell Carcinoma: A Narrative Review and Update.

Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition in MCC, the importance of immunotherapy and vaccines in MCC has increased in recent years. In this article, we aim to present the current progress and perspectives in the development of vaccines for this disease. Here, we summarize and discuss the current literature and ongoing clinical trials investigating vaccines against MCC. We identified 10 articles through a PubMed search investigating a vaccine against MCC. From the international clinical trial database Clinical.Trials.gov, we identified nine studies on vaccines for the management of MCC, of which seven are actively recruiting. Most of the identified studies investigating a vaccine against MCC are preclinical or phase 1/2 trials. The vaccine principles mainly included DNA- and (synthetic) peptide-based vaccines, but RNA-based vaccines, oncolytic viruses, and the combination of vaccines and immunotherapy are also under investigation for the treatment of MCC. Although the management of MCC is changing, when compared to times before the approval of immune checkpoint inhibitors, it will still take some time before the first MCC vaccine is ready for approval.

Abstract PO1-19-07: A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer

Abstract Background: Despite recent FDA approval of immune checkpoint inhibitor (ICI) and antibody-drug conjugates (ADCs), therapeutic options for metastatic triple negative breast cancer (mTNBC) remain limited. There is an unmet need to identify novel ICI combinations for improved efficacy. We recently demonstrated that ivermectin induces robust T cell infiltration into breast tumors and turning “cold” tumors “hot” in mouse model of TNBC. Balstilimab is a fully humanized IgG4 anti-PD-1 agent with proven safety and efficacy in metastatic cervical cancer. The current phase I/II trial is designed to test the safety and efficacy of the combination of ivermectin and balstilimab in patients with mTNBC. Methods: Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on 1-2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease. Eligible patients receive balstilimab 450 mg, IV, on Day 1 and ivermectin (30, 45 or 60 mg po daily), PO, Days 1-3, 8-10, 15-17 of each 21 days cycle till disease progression or intolerance. The primary objection of the phase 1 portion of the study is t determine the recommended phase 2 dose of ivermectin in combination with balstilimab using NCI-CTCAE v5.0. The primary objective of the phase II portion of the study is to determine the efficacy of the combination in mTNBC who are PD-L1 negative using the objective response rate (ORR). Secondary objectives are progression free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and patients’ quality of life (QOL) by EORTC QLQ-C30. Peripheral blood, tumor tissue and gut microbiome will be collected for correlative aims include pharmacokinetics, tumor microenvironment ICDs and gut microbiota in association with response to therapy. In the Phase 1 portion, eligible patients will be enrolled to one of three doses using the IQ 3+3 design. In the Phase 2 portion, patients will continue to be accrued to the RP2D (either the MTD or a lower dose depending on clinical judgement considering all the clinical and correlative data available). The Phase 2 portion will be conducted in two stages. In stage 1, a total of 13 PDL1-negative TNBC breast cancer patients will be treated at the RP2D. If there are no responders, the Phase 2 portion will close. With at least one responder, accrual may continue until 25 patients are accrued to the Phase 2 portion. If at least 3 responders are noted in 25 patients, this will be sufficient to consider the combination promising. This rule provides a type I error of 12% for a true response rate of 5%, and a power of 88% for true response rate of 20%. The estimated targeted accrual is 34-41 (Phase 1: 14-16; Phase 2: 20-25). Clinical trial information: NCT05318469 Citation Format: Yuan Yuan, Stephen Shiao, Mourad Tighiouart, Monica Mita, Jin-Sun Bitar, Philomena McAndrew, Park Dorothy, Maryliza El-Masry, Paul Frankel, Peter Lee. A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-07.

Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC

BackgroundThe use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to...

Abstract 2731: CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model

Abstract Background The approval of immune checkpoint inhibitors (ICI) such as PD-(L)1 inhibitors has revolutionized cancer therapy and established a role for immune effector cells, most notably CD8+ T cells, in tumor control and destruction. While anti-PD-(L)1 therapy has demonstrated durable responses, only a small subset of patients benefit and respond to therapy. CCR5 is expressed on multiple immune cells (e.g. myeloid-derived suppressor cells) and CCR5-dependent migration of these cells contribute to an immune-suppressive tumor microenvironment (TME) thereby limiting response to ICI therapy. In addition, expression of CCR5 on cancer cells has been linked to increased metastasis and resistance to ICI therapy. Upregulation of CCL5/CCR5 has been associated with poor outcomes in multiple solid tumor indications, including colorectal cancer (CRC). Therefore, targeting CCR5 has the potential to increase response rates to ICI therapy and improve outcomes. Herein, we describe a first-in-class CCR5 targeting DFC, CCR5-001, a multivalent conjugate of a potent, small molecule CCR5 antagonist conjugated to an immune-silent proprietary human IgG1 Fc. This CCR5 targeting DFC has the potential to improve responses to ICI therapy by preventing pro-tumorigenic reprogramming of the TME induced by CCL5/CCR5 expressing tumor and myeloid cells. Methods Binding of CCR5-001 to hCCR5 was measured by surface plasmon resonance (SPR) and to CCR5+ PathHunter cells (DiscoverX) by flow cytometry. Functional activity was determined in CCR5+ PathHunter β-arrestin assay with CCL3 to induce CCR5 signaling according to manufacturer’s instructions. Efficacy was determined in an immune-competent syngeneic mouse model using the CRC cell line, MC38. CCR5-001 was dosed at 20 mg/kg twice per week for two weeks. Tumor volumes were recorded and statistical analysis was conducted by t-test (Mann-Whitney) or two-way ANOVA in Prism. Results CCR5-001 displayed a KD of 4.2 nM to immobilized hCCR5 by SPR and IC50 of 0.63-0.98 nM for binding to engineered CCR5+ PathHunter cells. This high affinity binding translated to potent functional inhibition of CCL3-induced CCR5 signaling with an IC50 of 12.7 nM in CCR5+ cell-based assay. CCR5-001 demonstrated potent, statistically significant (p = 0.0052) tumor growth inhibition of 76% by day 13 in a syngeneic mouse model. Conclusions CCR5-001 demonstrated potent CCR5 binding and functional inhibition of CCR5 signaling in cell-based assays. The in vitro activity translated to robust efficacy as a monotherapy in a syngeneic mouse model. Based on these results and other emerging data, CCR5-001 represents an exciting new avenue for targeting CCR5 with DFCs in solid cancers where the pathology is driven by the CCR5/CCL5 axis. Citation Format: Simon Döhrmann, James Levin, Nicholas Dedeic, Amanda Almaguer, Doug Zuill, Elizabeth Abelovski, Jeffrey B. Locke, Joanne Fortier, Maria Hernandez, Qiping Zhao, Karin Amundson, Madison Moniz, Hongyuan Chen, Dhanya Panickar, Thanh Lam, Grayson Hough, Thomas P. Brady, Allen Borchardt, Jason N. Cole, Leslie W. Tari. CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2731.

Abstract 7539: First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity

Abstract NTX1088, a first-in-class anti-PVR (CD155) mAb, is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425). The trial initiated at MD Anderson Cancer Center, and was expanded into additional sites, including City of Hope, Ochsner Health, Sheba Medical Center and Hadassah Medical Center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 is investigated as a single agent and in combination with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with advanced solid malignancies. Ongoing dose escalation demonstrates a safe profile across ascending dose levels. NTX1088 is a high affinity humanized IgG4-S228P mAb that binds PVR and blocks all known interacting receptors at a single nM EC50. PVR, is a highly upregulated membrane protein on numerous tumor cells. PVR expression has been associated with worse patient outcome, due to its central role in immune suppression. PVR’s impact is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. PVR also interacts with the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088 has multiple immune-stimulating roles, through restoration of DNAM1 immune activation function, while simultaneously neutralizing TIGIT, CD96 and KIR2DL5A inhibitory signals in immune cells. Importantly, DNAM1 downmodulation was recently identified as a key resistance mechanism to approved immune checkpoint inhibitors, and its restoration by NTX1088 is a novel MoA, not demonstrated previously by other therapies.In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, superior to TIGIT, CD112R, and PD1 antibody blockade, leading to a greater immune-mediated tumor cell killing, IFNγ secretion, and CD137 induction. Importantly, only NTX1088 was able to restore DNAM1 to the surface of immune cells. Synergy was obtained when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13.Syngeneic models of PVRK.O, demonstrated a complete immune-mediated tumor regression. Numerous humanized murine xenograft models were investigated whereby NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade.In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on its ability to simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker analysis is showing initial mechanistic proof of concept for NTX1088 mode of action, including the restoration of DNAM1 surface expression on patients’ immune cells. This is the first case of surface DNAM1 elevation in clinical settings. Citation Format: Anas Atieh, Akram Obeidat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana Roviš, Paola Brilc, Ofer Mandelboim, Stipan Jonjic, Pini Tsukerman. First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7539.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma.

Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.

Approved immune checkpoint inhibitors in hepatocellular carcinoma: a large-scale meta-analysis and systematic review

A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26–4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62–0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68–0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63–0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97–1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67–1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62–2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97–1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55–2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34–1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66–0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61–0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US

While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

The Financial Burden of Guideline-recommended Cancer Medications for Metastatic Urothelial Carcinoma

Bladder cancer is a significant global health concern owing to its prevalence, negative impact on quality of life, and high treatment costs. Treatment for metastatic urothelial carcinoma (mUC) traditionally relies on platinum-based chemotherapy regimens. However, clinical trial results have led to the approval of immune checkpoint inhibitors (ICIs) as viable treatment options. We assessed the escalating costs and economic viability of mUC treatment guidelines in Europe. We used a pragmatic approach that involved: (1) collection of the costs of the recommended medications in the five most populous European countries; (2) conversion of the costs into international dollars to account for differences in purchasing power parity among countries; (3) evaluation of the cost trends over time; and (4) comparison of the medication costs to World Health Organization thresholds. Introduction of ICIs in European guidelines substantially increased the cost of medications for mUC. Intriguingly, important differences across European countries emerged: the annual cost of medications was twofold higher in Italy than in France and the UK. Despite limitations, our study sheds light on the escalating costs and economic challenges of mUC treatment, and highlights the need for assessments of sustainable and cost-effective management approaches. Patient summaryWe looked at the costs of treatments for metastatic bladder cancer and found that costs have been rising over time, especially with the introduction of new immune therapies, with notable differences among European countries. While these new treatments improve patient outcomes, they also come with a high price tag, which could strain health care budgets. Our results suggest that cost-effectiveness studies will be essential in determining the best and most sustainable treatment strategies in the future.

Current status and future perspective of immunotherapy for renal cell carcinoma.

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives.