Use Of Immune Checkpoint Inhibitors Research Articles

Effect of immune checkpoint inhibitors at different treatment time periods on prognosis of patients with extensive-stage small-cell lung cancer.

The application of immune checkpoint inhibitors (ICIs) in treating patients with extensive-stage small-cell lung cancer (ES-SCLC) has brought us new hope, but the real-world outcome is relatively lacking. Our aim was to investigate the clinical use, efficacy, and survival benefit of ICIs in ES-SCLC from real-world data analysis. A retrospective analysis of ES-SCLC patients was conducted between 2012 and 2022. Progression-free survival (PFS) and overall survival (OS) were assessed between groups to evaluate the value of ICIs at different lines of treatment. PFS1 was defined as the duration from initial therapy to disease progression or death. PFS2 was defined as the duration from the first disease progression to the second disease progression or death. One hundred and eighty patients with ES-SCLC were included. We performed landmark analysis, which showed that compared to the second-line and subsequent-lines ICIs-combined therapy group (2SL-ICIs) and non-ICIs group, the first-line ICIs-combined therapy group (1L-ICIs) prolonged OS and PFS1. There was a trend toward prolonged OS in the 2SL-ICIs group than in the non-ICIs group, but the significance threshold was not met (median OS 11.94months vs. 11.10months, P = 0.14). A longer PFS2 was present in the 2SL-ICIs group than in the non-ICIs group (median PFS2 4.13months vs. 2.60months, P < 0.001). First-line ICIs plus chemotherapy should be applied in clinical practice. If patients did not use ICIs plus chemotherapy in first-line therapy, the use of ICIs in the second line or subsequent lines of treatment could prolong PFS2.

Immune checkpoint inhibitor colitis, a rising issue in targeted cancer therapy era: A literature review.

Research advances in the oncology treatment field have led to the widespread use of immunotherapy. The usage of immune checkpoint inhibitor (ICI) has improved the survival of cancer patients with metastases. This has also led to the rapidly expanding indications for ICI use. However, ICI usage may lead to toxicity, which may be immune-related, in different organ-specific targets. The immune-related adverse events (irAEs) of ICI may lead to increased morbidity, decreased quality of life, and early termination of ICI. The clinical manifestations of irAEs in the gastrointestinal system are variable, ranging from self-limited to life-threatening or fatal events. In this review article, we would like to focus on discussing ICI-induced colitis, which is one of the most common ICI irAEs in the gastrointestinal tract.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Immune checkpoint inhibitors combined with paclitaxel-based chemotherapy versus chemotherapy alone as first-line treatment in HER2-negative advanced gastric cancer: result of a multicenter retrospective study.

Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Predictors of Immunotherapy Efficacy in Metastatic Non-Small Cell Lung Cancer: Lung Immune Prognostic Index and Immune-Related Toxicity.

Immune checkpoint inhibitors (ICIs) have been proposed as the standard first-line and subsequent treatment for metastatic non-small cell lung cancer (NSCLC). This study analyzed whether patients with good lung immune prognostic index (LIPI) have a better response to ICIs and the relationship between immune-related adverse events (irAEs) and response in clinical practice. This was an observational, retrospective, single-center study. Patients with stage IV NSCLC between 2016 and 2021 were included in the study. Toxicity was assessed according to The Common Terminology Criteria for Adverse Events. Response assessment was performed according to RECIST 2.0 and immuno-related criteria. Descriptive and survival analyses were conducted. Degree of toxicity and response to treatment (based on treatment and histology) were assessed. LIPI and response were assessed. LIPI included dNLR (absolute neutrophil count/(white blood cell count - absolute neutrophil count)) ≥ 3 and lactate dehydrogenase (LDH) greater than the upper limit of normal. Patients were stratified into good (G), intermediate (I), and poor (P) prognostic groups. A total of 168 patients were included (130 men and 38 women, mean age 64.3 years). ICI use in the first- or second-line treatment was 65% and 35%, respectively. Fifteen (9%) patients showed complete response (CR), 50 (30%) showed partial response (PR), 39 (22%) had stable disease (SD), 45 (28%) had progressive disease (PD), and 19 (11%) were not evaluated (NE). Patients with good prognostic LIPI (dNLR < 3 and normal LDH levels) showed a better response. Progression-free survival (PFS) was 19 months in G, 6 months in I, and 2 months in P. Overall survival (OS) was 27 months in G, 8 months in I, and 3 months in P. One hundred fourteen patients died (56% G, 76% I, 93% P). Patients with adenocarcinoma were 116 (77 with irAEs G1-4 (13 CR, 31 PR, 21 SD, eight PD, and four NE)), and without were 39 (three PR, six SD, 21 PD, and nine NE). Fifty-two patients had squamous carcinoma (27 with irAEs G1-4 (two CR, 12 PR, nine SD, and four PD)), and 25 did not (four PR, three SD, 12 PD, and six NE)). IrAEs appearance was observed in longer PFS (19 vs. 2 months) and OS (27 vs. 4 months; P < 0.0001). LIPI was a positive predictor of response to ICI. The presence of irAEs is associated with a better immune response. In contrast, the absence of toxicity predicted a worse prognosis.

Clinical outcomes after use of checkpoint inhibitor immunotherapies in people with multiple sclerosis.

Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited. To characterize outcomes in a cohort of adults with MS who received ICIs. A single-center retrospective review of medical record data was performed for people with MS treated with ICIs. Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13). In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.

Cost-effectiveness of immune checkpoint inhibitors in treating metastatic urothelial cancer.

Objectives: Immune checkpoint inhibitor (ICI) is an important treatment option for metastatic urothelial carcinoma (mUC) patients. A lot of clinical evidence proved the survival benefits of ICI, but cost-effectiveness of the treatment remains unclear. This study evaluates the cost-effectiveness of the ICIs treatment in different sequences among mUC patients. Methods: We retrospectively analyzed mUC patients who had been treated at our hospital between January 2016 and December 2020. These patients received chemotherapy with or without ICI treatment (Pembrolizumab, Atezolizumab, Nivolumab, Durvalumab, or Avelumab). The patients were divided into three different groups: receiving chemotherapy alone, receiving a combination of first-line ICI and chemotherapy (ICI combination therapy), and receiving chemotherapy as the first-line treatment followed by second-line ICI therapy (Subsequent ICI therapy). The primary endpoint was cost per life day, while lifetime medical costs and overall survival were also evaluated. Results: The 74 enrolled patients had a median age of 67.0 years, with 62.2% being male. Of these patients, 23 had received chemotherapy only, while the remaining patients had received combined therapy with ICI in either first-line or as subsequent agents (37 patients had ever received atezolizumab, 18 pembrolizumab, 1 Durvalumab, 1 Nivolumab, and 1 Avelumab separately.). Fifty-five patients (74.3%, 55/74) received cisplatin amongst all the patients who underwent chemotherapy. Median overall survival was 27.5months (95% CI, 5.2-49.9) in the first-line ICI combination therapy group, and 8.9months (95% CI, 7.1-10.8) in the chemotherapy only. Median overall survival for the subsequent ICI therapy group was not reached. The median lifetime cost after metastatic UC diagnosis was USD 31,221. The subsequent ICI therapy group had significantly higher costs when compared with the ICI combination therapy group (155.8 USD per day, [IQR 99.0 to 220.5] v 97.8 USD per day, [IQR 60.8 to 159.19], p = 0.026). Higher insurance reimbursement expenses for the subsequent ICI therapy group were observed when compared with the ICI combination therapy group. Conclusion: Our real-world data suggests that first line use of ICI combined with chemotherapy demonstrates better cost-effectiveness and similar survival outcomes for mUC patients, when compared with subsequent ICI therapy after chemotherapy.

Side Effects and Research Progress of Immune Checkpoint Inhibitors

Immune checkpoint inhibitor (ICI) is a new type of tumor treatment drug, also known as immunotherapy drug. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. The use of immune checkpoint inhibitors can help control or treat certain types of cancer by promoting the restoration of inactivated immune cells and enhancing the immune system's ability to attack. -This article focuses on skin reactions, immune pneumonitis, and adverse reactions in the thyroid and digestive tract. Through the analysis of recent relevant research, this question summarizes several different side effects, their causes and treatments. Although there are many treatments to deal with the side effects of this drug, it is important to note that the side effects of this drug are not always well understood. There are many treatments to deal with the related side effects, these side effects are still a barrier to the current use of ICIs. Future development directions should focus more on the development of ICIs. directions should focus more on the development of new targets, optimization of drug pharmacokinetics, and alleviation of side effects caused by ICIs.

Abstract 912: CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study

Abstract Background: Immune Checkpoint Inhibitors (ICIs) are a cornerstone in the treatment of cancers such as Non-Small Cell Lung Cancer (NSCLC). Despite the standard use of biomarkers such as PD-L1 expression for selecting ICI regimens, recent studies suggest missed opportunities for benefit in PD-L1 low/negative patients. Therefore, there is an urgent need for new biomarker strategies capable of guiding the use of ICIs in NSCLC. We introduce and validate an AI-powered radiology tool for ICI patient selection that provides interpretable predictions by quantifying aspects of tumor biology on baseline CT scans directly associated with ICI efficacy, such as tumor heterogeneity and twistedness of the tumor-associated vasculature. Methods: We analyzed CT scans of 439 patients treated with ICI at 4 institutions (D1-D4) using the Picture Health Px platform. Experienced radiologists and physicians across institutions delineated target lesions on baseline CT scans. A deep learning model was used to segment pulmonary vessels. CheckpointPx v1.11, an interpretable neural network incorporating quantitative features extracted from within the tumor and its vasculature, was trained to predict ICI response (defined as disease control per RECIST best overall response) on n=247 patients (D1-D3). It was assessed with respect to response and progression free-survival (PFS) on 192 patients (D2-D4), with D4 (n=105) being an external validation set. CheckpointPx was also evaluated within PDL1 subsets among testing set patients where available (n=138). Results: The cohort was predominantly late stage (Stage 3/4) (&amp;gt;85%) and was mixed with respect to ICI line of treatment (1st-4th). 122 of 247 (49%) and 119 of 192 (62%) were responders in training and test cohorts respectively. CheckpointPx included 16 features, such as entropy-based heterogeneity and quantitative vessel tortuosity (twistedness). The model predicted response to ICI with an AUC=0.65 on the test set. The CheckpointPx High Risk group significantly stratified patients by PFS (HR=1.67 [1.22-2.28], p=0.001). This separation remained significant within the subset of PDL1-negative (HR=2.71 [1.35-5.44], p=0.005) and PDL1-positive patients (HR=2.05 [1.22-3.46], p=0.007). Conclusions: From baseline radiology, CheckpointPx was shown to strongly predict ICI outcomes across multiple institutions, NSCLC stages, and lines of ICI. Furthermore, the tool stratified patients by ICI benefit within both PDL1-positive and negative subsets - suggesting the potential of CheckpointPx to address critical gaps in the NSCLC biomarker landscape. CheckpointPx is driven by interpretable imaging biomarkers, and thus its predictions are tied to specific and quantifiable phenotypic attributes of the tumor and its microenvironment. Citation Format: Amogh Hiremath, Seyoung Lee, Jeeyeon Lee, Peter Haseok Kim, Kai Zhang, Salie Lee, Monica Yadav, Maria Jose Aguilera Chuchuca, Taegyu Um, Myungwoo Nam, Liam Il-Young Chung, Hye Sung Kim, Jisang Yu, Trie Arni Djunadi, Leeseul Kim, Youjin Oh, Sungmi Yoon, Zunairah Shah, Yuchan Kim, Ilene Hong, Grace Kang, Jessica Jang, Amy Cho, Soowon Lee, Cecilia Nam, Timothy Hong, Yury S. Velichko, Amit Gupta, Vamsidhar Velcheti, Anant Madabhushi, Nathaniel Braman, Young Kwang Chae. CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study [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 912.

Abstract 700: Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response

Abstract Background: Colorectal cancers (CRC) that are deficient for DNA mismatch repair (dMMR) proteins have high levels of genetic instability and consequently high mutational burden, creating numerous neoantigens that can elicit an immune response. Therefore, dMMR CRC are the best candidates for immune checkpoint inhibition (ICI) compared to proficient DNA mismatch repair (pMMR) CRC. Early clinical trials revealed that only 30-55% metastatic dMMR CRC responded to ICI. Recent studies utilizing allograft models have demonstrated that tumor immune landscape can be primed with radiopharmaceutical therapy (RPT). Although early results have been quite promising, allograft models often fail to accurately predict efficacy for many reasons, but most often are due to a lack of heterogeneity. Methods: To better understand how heterogenous MMR expression impacts tumor development and response to ICI alone or in combination with RPT, we developed a new mouse model that develops three tumor types: (1) homotypic dMMR tumors that express green fluorescent protein, (2) homotypic pMMR tumors that express red fluorescent protein, and (3) heterotypic tumors with a mixture of dMMR and pMMR cells. Surveillance bright field and fluorescent colonoscopies allow us to assess treatment response by measuring tumor size and proportion of dMMR and pMMR tumor cells in real-time. These outcomes are verified through ex vivo imaging and histological analysis. Results: Tumor response to anti-PD-L1 ICI was dependent on MMR status. Homotypic dMMR tumors exhibited the strongest response: significantly smaller in treated mice than controls, exhibited areas of vascular congestion and increased CD8+ cytotoxic T-cells infiltration. Response of heterotypic MMR tumors varied depending on percentage of dMMR cells; tumors with a high percentage of dMMR cells remained small, whereas tumors with a low percentage of dMMR had an outgrowth of pMMR cells. Treated and untreated homotypic pMMR tumors were indistinguishable. To enhance the response of all three tumor types, mice were treated with dual ICI treatment, anti-PD-L1 and anti-CTLA-4, or RPT. Animals administered the tri-therapy (dual ICI + RPT) survived significantly longer with fewer tumors than animals treated with either dual ICI or RPT alone. Conclusions: Our innovative mouse model allows for the highly detailed characterization of tumor response to therapies. Simplistic allograft models may not adequately account for the dynamic effects that neighboring cell death may have on radio-resistant cells, on tumor vascular perfusion and oxygenation, or on tumor immune infiltration and adaptive immune recognition of remaining cells. We begin to fill these critical gaps in knowledge and therefore the results from our studies will help guide the translation and integrated use of ICIs and RPTs in clinic. Citation Format: Santina M. Snow, Dawn Albrecht, Paul A. Clark, Caroline P. Kerr, Joseph J. Grudzinski, Justin J. Jeffery, Hansel Comas Rojas, Reinier Hernandez, Kristina A. Matkowskyj, Jamey P. Weichert, Zachary S. Morris, Richard B. Halberg. Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response [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 700.

Abstract 1426: Lipid-mediated epigenetic activation of PPAR-gamma signaling promotes immune-checkpoint resistance in hepatocellular carcinoma

Abstract Background: Although use of immune-checkpoint inhibitors (ICI) has yielded impressive results in cancer patients, resistance to ICI therapies has increasingly been observed, especially in hepatocellular carcinoma (HCC). Materials and Methods: We generated a novel anti-programmed death-ligand 1 (PD-L1) treatment resistant mouse hepatoma cell Hepa1-6 (PD-L1R) by 7-generation of in vivo selection. To dissect tumor cell-intrinsic resistant mechanism, we performed single-cell RNA-sequencing (scRNA-seq) from anti-PD-L1-treated tumors generated from parental or PD-L1R cells. Expression level of target genes was detected by QPCR, western blot and immunohistochemical analyses. Lipid content and fatty acid uptake was examined by Oil Red O and BIODIPY staining. Peroxisome proliferator-activated receptor gamma (PPARγ) promoter methylation level was analyzed by bisulfite pyrosequencing. To investigate the tumor cell-extrinsic factors, we profiled the myeloid and lymphoid lineages by flow cytometry. Results: ScRNA-seq revealed significant gene enrichments in lipid metabolism and PPARγ signaling pathway in PD-L1R tumors, which could be verified in both mRNA and protein levels. Moreover, we observed evident lipid accumulation in the PD-L1R tumors when compared to the parental tumors by Oil Red O staining. Consistently, PD-L1R tumor cells exhibited higher lipid content and enhanced fatty acid uptake in vitro, as demonstrated by BODIPY493/503 and BODIPY-C16 analyses. Of note, palmitic acid could dose-dependently increase Pparg mRNA expression in parental cells to a similar level with the PD-L1R cells, supporting an important role of lipids in inducing PPARγ expression. Pyrosequencing analysis indicated that PD-L1R cells exhibited lower PPARγ methylation level compared with parental cells. Notably, 5-Azacytidine treatment in parental cells significantly reduced the promoter DNA methylation and increased Pparg mRNA expression to similar extent with the PD-L1R tumor cells, thus indicating DNA hypomethylation-driven PPARγ up-regulation. Flow cytometry analysis showed that ICI resistance was associated with lower cytotoxic CD8+ T cells but higher intermediate Th17 cells, myeloid-derived suppressor cells and T regulatory cells in the tumor microenvironment (TME). Conclusions: Our study suggested that lipid exposure may epigenetically up-regulate PPARγ transcription in the development of anti-PD-L1 resistance. Detailed investigation on the crosstalk between aberrant lipid metabolism and immunosuppressive TME is ongoing. Acknowledgment: This study is supported by RGC General Research Fund (14120621 and 14119023), Li Ka Shing Foundation and CUHK Strategic Seed Funding for Collaborative Research Scheme. Citation Format: Zhewen Xiong, Stephen Lam Chan, Jingying Zhou, Xuezhen Zeng, Weiqin Yang, Haoran Wu, Jianquan Cao, Jie-Ting Low, Michael Wing-Yan Chan, Kevin Yuk-Lap Yip, Joseph Jao-Yiu Sung, Alfred Sze-Lok Cheng. Lipid-mediated epigenetic activation of PPAR-gamma signaling promotes immune-checkpoint resistance in hepatocellular carcinoma [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 1426.

Abstract 7474: T-cell responses across heart, blood, and tumor in patients with immune checkpoint inhibitor-related myocarditis (irMyocarditis)

Abstract Introduction: Immune checkpoint inhibitor (ICI)-related myocarditis (irMyocarditis) is a potentially lethal complication of ICI use that is characterized by the presence of clonally expanded T cells in the heart. The antigens recognized by these expanded intracardiac T-cell clones and their relationships to T-cell clones in the blood and tumors of irMyocarditis patients are poorly understood. Methods: Paired single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) sequencing was performed on heart tissue (n = 13) and peripheral blood from patients with irMyocarditis (n = 25) and ICI-treated controls (n = 28) using the 10X Chromium (10X Genomics) system. TCR-β chain sequencing was performed (Adaptive Biotechnologies) on four autopsy cases of patients with available scRNA-seq data and irMyocarditis heart, tumor, and histologically normal tissue. An established high-throughput protocol was used to screen expanded intracardiac TCRs against candidate antigens (Oliveira G, et al. Nature 2021). Briefly, full-length TCRs were cloned, transduced into donor T cells, and screened against autologous or major histocompatibility complex (MHC) Class I-matched antigen presenting cell lines pulsed with peptide pools that covered the full length of the ⍺-myosin, troponin-I, and troponin-T proteins alongside pools of common viral antigens and appropriate controls. Results: scRNA-seq data showed that TCRs shared between heart and blood are predominantly found in circulating CD8 T cell subsets as compared to circulating CD4 T cell subsets. The gene expression patterns of these shared T-cell clones in circulation appear distinct in fatal and non-fatal irMyocarditis patients, with shared T-cell clones in fatal cases expressing cycling markers (MKI67, STMN1) and the chemokine receptor CXCR3. TCR-β chain sequences most enriched in irMyocarditis tissue relative to control tissues were distinct from those enriched in tumor tissues, and their full-length TCR sequences could be recovered from scRNA-seq data. In total, 52 cardiac-expanded TCRs across eight donors were screened against candidate antigens. None of the screened TCRs recognized the putative cardiac autoantigens. Conclusions: T-cell clones expanded in irMyocarditis are shared in circulation, where the gene expression of these clones may help to distinguish fatal from non-fatal irMyocarditis. TCRs enriched in irMyocarditis appear to be largely distinct from those enriched in tumor and likely recognize currently unknown cardiac autoantigens. Citation Format: Steven Blum, Daniel A. Zlotoff, Neal P. Smith, Isabela J. Kernin, Swetha Ramesh, Giacomo Oliveira, Leyre Zubiri, Joshua Caplin, Nandini Samanta, Sidney Martin, Mike Wang, Alice Tirard, Pritha Sen, Yuhui Song, Katherine Xu, Jaimie L. Barth, Kamil Slowikowski, Mazen Nasrallah, Jessica Tantivit, Kasidet Manakongtreecheep, Benjamin Y. Arnold, John McGuire, Alexander B. Afeyan, Christopher J. Pinto, Daniel McLoughlin, Monica Jackson, PuiYee Chan, Aleigha Lawless, William A. Michaud, Tatyana Sharova, Linda T. Nieman, Justin F. Gainor, Dejan Juric, Mari Mino-Kenudsen, Ryan J. Sullivn, Genevieve M. Boland, James R. Stone, Catherine J. Wu, Molly F. Thomas, Tomas G. Neilan, Kerry L. Reynolds, Alexandra-Chloé Villani. T-cell responses across heart, blood, and tumor in patients with immune checkpoint inhibitor-related myocarditis (irMyocarditis) [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 7474.

Abstract 2468: Phase II study of cryoablation and post-progression immune checkpoint inhibition in metastatic melanoma

Abstract Introduction: Efforts to overcome resistance to immune checkpoint inhibition (ICI) are paramount, and novel combination strategies are in development. Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment that has demonstrated immune modulatory effects. We hypothesized that cryoablation may prime the tumor microenvironment (TME) through direct modulation of the tumor, thereby generating an anti-tumor response in ICI refractory tumors. Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoint was safety and feasibility, with objective response rate (ORR) and disease control rate (DCR) in non-ablated lesions a key secondary endpoint. To better understand the inflammatory state of TME as well as factors determining response to cryoablation, we performed immunohistochemistry (PD-L1, CD8+ TIL) as well as single-cell RNA-sequencing (ScRNAseq) on evaluable pre- and post-cryoablation biopsies obtained from metastatic sites of 15 patients. Results: From May 2018 through July 2020, 17 patients were treated. This regimen was feasible with all patients ongoing cryoablation with no unexpected safety signal. The ORR and DCR was 23.5% (95% CI 6.81-49.9) and 41.2% (95% CI 18.44-67.08), respectively, with four patients experiencing PR and three patients SD. Durable control, defined as tumor control ≥6 months, was achieved in 35%. Median progression-free survival (PFS) was 59 days (95% CI 42, 179) with a 6-month PFS rate of 23.5% (95% CI 7.3%, 44.9%). Median overall survival (OS) was 387 days (95% CI 106, 608) with a 1-year OS rate of 53% (95% CI (27.6%, 73%). Correlative analysis demonstrated pre-ablation tumors were uniformly associated with a “cold” TME, as all samples were PD-L1 negative and the majority had low levels of CD8+ TIL, defined as ˂5% of tumor cells associated with CD8+ TILs. ScRNAseq revealed no clear trends of cell type composition to predict best response to cryoablation, however an increase in B/plasma cells was seen in patients with disease control, suggesting these cells may play a role in mounting a durable anti-tumor response after cryoablation. Conclusion: The anti-tumor efficacy of combining cryoablation and post-progression ICI was superior to what would be expected with the use of post-progression ICI alone with an acceptable safety profile. Our data support further study of this novel, synergistic therapeutic approach. Citation Format: Meghan J. Mooradian, Florian J. Fintelmann, Thomas J. LaSalle, Judit Simon, Alexander Graur, Alona Muzikansky, Mari Mino-Kenudson, Sophia Shalhout, Howard L. Kaufman, Russell W. Jenkins, Donald Lawrence, Aleigha Lawless, Tatyana Sharova, Raul N. Uppot, Jacy Fang, Emily M. Blaum, Anna L. Gonye, Irena Gushterova, Genevieve M. Boland, Nir Hacohen, Moshe Sade-Feldman, Ryan J. Sullivan. Phase II study of cryoablation and post-progression immune checkpoint inhibition in metastatic melanoma [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 2468.

The abscopal effect: mechanism of occurrence and prospects of using it in therapy of metastatic cancer

The abscopal effect in oncology has been known for 70 years, but until recently its clinical significance was rather low. The development of immune response checkpoint inhibitors has led to an active study of this phenomenon. There is now evidence of improved survival among patients, in whom the abscopal effect has been documented, opening new perspectives for the treatment of cancers at different stages. This review presents data on the mechanisms of the abscopal effect, experimental and clinical data, current limitations and possible perspectives. The aim of the study was to investigate the current concept of the abscopal effect occurrence and to evaluate the prospects of using the abscopal effect in therapy of metastatic cancer. Material and Methods. We searched publications in Pubmed system from 2010 to 2023. Of 286 publications, 72 were used for writing the review. Results. In the era of widespread use of immune checkpoint inhibitors (ICIs) for cancer therapy, the abscopal effect appears to be an effective therapeutic approach with broad prospects of application in the treatment of patients with metastatic cancer. Conclusion. The incidence of the abscopal effect has increased with the advent of immune therapy, and the use of ICIs with radiation therapy (RT) has shown improved survival even in patients with advanced disease. More research is needed to establish standardized treatment protocols, including the optimal dose and timing of RT, as well as the efficacy and safety of combination therapy with different classes of ICIs. Further search for clinical and laboratory abscopal effect predictors, which could allow personalized treatment approaches, is required.

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors.

Immune-related adverse events (irAEs) are the most common complication of immune checkpoint inhibitor (ICI) therapy. With the widespread use of ICIs in patients with solid tumors, up to 40% of the patients develop irAEs within five months of treatment, and 11% develop severe irAEs requiring interventions. A predictive test for irAEs would be a crucial tool for monitoring for complications during and after ICI therapy. We performed an extensive review of potential predictive biomarkers for irAEs in patients who received ICI therapy. Currently, only thyroid-stimulating hormone is utilized in common clinical practice. This is due to the unavailability of commercial tests and unclear predictive values from various studies. Given the lack of single strong predictive biomarkers, some novel approaches using composite scores using genomic, transcriptomics, cytokine levels, or clinical parameters appear appealing. Still, these have yet to be validated and incorporated into clinical practice. Further research conducted to validate the models before implementing them into real-world settings will be of the utmost importance for irAE prediction.

C-reactive protein flare predicts response to checkpoint inhibitor treatment in melanoma.

The treatment of melanoma has been revolutionized by the use of immune checkpoint inhibition (ICI), but many patients do not benefit. Furthermore, immune-related adverse events may occur during therapy. A predictive biomarker is needed to reliably identify patients benefitting. In lung, renal cell and bladder cancer early C-reactive protein (CRP) kinetics were shown to be a predictive biomarker for ICI. Here, we investigate early CRP kinetics as predictive biomarker for ICI in melanoma patients. Two independent prospectively collected cohorts were analysed: Cohort 1 (n = 87) with advanced and Cohort 2 (n = 99) with completely resected melanoma. Patients were stratified by in the dynamics of CRP after ICI initiation: A doubling of baseline CRP within 30 days followed by at least a 30% drop within 3 months was classified as a CRP flare. If no doubling of CRP was reported, but a 30% drop within 3 months, patients were classified as CRP responders and all others as CRP non-responders. Analysed factors included clinical characteristics like S100B and LDH. Median follow-up was 1.5 and 1.7 years for Cohorts 1 and 2. In Cohort 1 CRP flare (n = 12), CRP responders (n = 43) and CRP non-responders (n = 32) with a progression-free survival (PFS) of 0.7, 0.6 and 0.2 years (p = 0.017) and an overall survival (OS) of 2.2, 1.5 and 1.0 years (p = 0.014), respectively. Multivariable Cox analysis showed an independent risk reduction of progression for CRP responders by 62% compared to CRP non-responders (p = 0.001). In Cohort 2 CRP flare (n = 13), CRP responders (n = 70) and CRP non-responders (n = 16) the log-rank analysis showed a significant difference between OS and recurrence-free survival (RFS) curves (p = 0.046 and p = 0.049). Early CRP kinetics could indicate a response to ICI with improved OS and RFS/PFS. CRP flare and CRP response indicating significantly improved outcomes compared to CRP non-responders.

Fine-tuning tumor- and allo-immunity: advances in the use of immune checkpoint inhibitors in kidney transplant recipients.

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.

Immune checkpoint inhibitors in high-grade upper tract urothelial carcinoma: Paradigm shift emphasizing organ preservation.

The aim was to evaluate the role of immune check point inhibitors (ICIs) in patients with high-grade upper tract urothelial carcinoma (UTUC) who are managed endoscopically when nephroureterectomy (NU) is not feasible, such as in patients who are either not candidates for NU or decline extirpative surgery. All patients diagnosed with high-grade UTUC and managed endoscopically between January 1996 and August 2022 were included in the study. Subsequently, patients were categorised based on their use of ICIs into group 1 (patients who did not receive ICIs) and group 2 (patients who received ICIs). Survival outcomes were assessed using Kaplan-Meier analysis, while a multivariable regression model was employed to analyse the impact of clinical characteristics on survival. A total of 29 patients were enrolled, with 14 in group 1 and 15 in group 2. Both groups exhibited similar demographic and disease characteristics, including multifocality, laterality and initial tumour size. The median follow-up period was 29.2months. Notably, group 2 demonstrated significantly enhanced overall and metastasis-free survival rates compared to group 1. At 47.8months, the overall survival rate was 0% (all patients died) in group 1, whereas it was 85.7% in group 2. Similarly, the metastasis-free survival rate was 0% (all patients had metastatic disease) in group 1 at 40.6months, whereas it reached 78.0% in group 2. The multivariable analysis indicated a correlation between ICI usage and improved survival outcomes, with a hazard ratio of 0.002. Utilisation of adjuvant ICIs in the setting of endoscopically treated patients with high-grade UTUC is associated with significantly improved survival rates. ICIs should be considered in this patient population, however, more studies with larger sample size are warranted.

Association of Timely Comprehensive Genomic Profiling With Precision Oncology Treatment Use and Patient Outcomes in Advanced Non-Small-Cell Lung Cancer.

Timely biomarker testing remains out of reach for many patients with advanced non-small-cell lung cancer (aNSCLC). Here, we studied the quality-of-care implications of closing the gap in timely receipt of comprehensive genomic profiling (CGP) to inform first-line (1L) decisions. Using a real-world clinicogenomic database, we studied testing and 1L treatment patterns in aNSCLC after the approval of pembrolizumab in combination with pemetrexed and carboplatin (May 10, 2017). To estimate the association of timely CGP results with therapy selection and patient outcomes, we identified patients with no previous genomic testing beyond PD-L1 immunohistochemistry and dichotomized patients by whether CGP results were available before or after 1L therapy initiation. In total, 2,694 patients were included in the 1L therapy decision impact assessment. Timely CGP increased matched targeted therapy use by 14 percentage points (17% with CGP v 2.8% without) and precision immune checkpoint inhibitor (ICPI) use by 14 percentage points (18% with CGP v 3.9% without). Receipt of timely CGP resulted in an estimated 31 percentage point decrease in ICPI use among ALK/EGFR/RET/ROS1-positive patients at an expected per-patient reduction in ineffective ICPI therapy cost of $13,659.37 with timely CGP to inform 1L treatment selection. Patient benefit of CGP extended to real-world time to therapy discontinuation (median time to therapy discontinuation: 3.9 v 10 months [hazard ratio, HR, 0.54 [95% CI, 0.42 to 0.70]; P = 1.9E-06; adjusted hazard ratio [aHR], 0.50 [95% CI, 0.38 to 0.67]; P = 2.0E-06) in 1L driver-positive patients. This effect was not significant for real-world overall survival (median overall survival: 32 v 29 months [HR, 1.2 [95% CI, 0.84 to 1.67]; P = .33; aHR, 1.4 [95% CI, 0.92 to 1.99]; P = .12). Timely CGP is associated with the quality of patient care as measured by 1L matched targeted therapy use, time to therapy discontinuation, and avoidance of ineffective, costly ICPIs.