Immune-related Toxicities Research Articles

Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16–0.88) and OR: 0.63 (95% CI 0.35–0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

Glatiramer Acetate Complexes CpG Oligodeoxynucleotides into Nanoparticles and Boosts Their TLR9-Driven Immunity.

Unmethylated cytosine-guanine oligodeoxynucleotides (CpG ODNs) have a storied history as agonists for Toll-like receptor 9 (TLR9). CpG ODNs have shown promising antitumor effects in preclinical studies by inducing potent proinflammatory immune responses. However, clinical success has been hindered by inconsistent efficacy and immune-related toxicities caused by systemic exposure to CpG ODNs. We previously identified that glatiramer acetate (GA), an FDA-approved, lysine-rich polypeptide, could complex class B CpG into cationic nanoparticles which persist at the intratumoral injection site while mitigating the induction of systemic proinflammatory cytokines in mouse tumor models. To extend GA applications across subtypes of CpG ODN (class A, B, and C), we evaluated physiochemical properties and identified the immunological signaling of GA and its complexes with different classes of CpG ODNs. We compared the physiochemical characteristics of three types of GA-CpG nanoparticles, followed by assessments of cell uptake efficiency and endolysosomal trafficking. We then performed successive in vitro and in vivo assays to evaluate immunological discrepancies. Complexation with GA preserved the immunological activity of CpG ODN subtypes while encapsulating them into cationic spherical nanoparticles. GA improved the cellular uptake of CpG ODNs, generally increased retention in early endosomes, and amplified immunological responses. A subsequent in vivo experiment confirmed the achievement of potent tumor suppression while mitigating systemic immune-related toxicities. Together, these data help elucidate the noncanonical role of GA to serve as a nucleic acid delivery scaffold that can improve the efficacy and safety of CpG adjuvant for clinical cancer immunotherapy.

Checkpoint inhibitor therapy: Immune-related adverse event management.

Treatment with immune checkpoint inhibitors for cancer is associated with a high prevalence of multiple immune-related toxicities. Immune-related adverse events (irAEs) can occur anytime during treatment and up to 3 months after treatment. This article discusses checkpoint inhibitor therapy and describes the implementation of a patient education program focused on recognizing immunotherapy irAEs and their toxicities.

CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients willbenefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Tumor necrosis factor superfamily signaling: life and death in cancer.

Immune checkpoint inhibitors have shaped the landscape of cancer treatment. However, many patients either do not respond or suffer from later progression. Numerous proteins can control immune system activity, including multiple tumor necrosis factor (TNF) superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) members; these proteins play a complex role in regulating cell survival and death, cellular differentiation, and immune system activity. Notably, TNFSF/TNFRSF molecules may display either pro-tumoral or anti-tumoral activity, or even both, depending on tumor type. Therefore, TNF is a prototype of an enigmatic two-faced mediator in oncogenesis. To date, multiple anti-TNF agents have been approved and/or included in guidelines for treating autoimmune disorders and immune-related toxicities after immune checkpoint blockade for cancer. A confirmed role for the TNFSF/TNFRSF members in treating cancer has proven more elusive. In this review, we highlight the cancer-relevant TNFSF/TNFRSF family members, focusing on the death domain-containing and co-stimulation members and their signaling pathways, as well as their complicated role in the life and death of cancer cells.

Successful use of therapeutic plasma exchange for the management of acute lung transplant rejection secondary to immune checkpoint inhibitor therapy

The use of immune checkpoint inhibitors (ICIs) in individuals with a history of solid organ transplantation is fraught with the emergence of solid organ transplantation rejection (SOTR). The current recommendations for the management of SOTRs secondary to ICI include the use of high-dose steroids along with the escalation of immunosuppressive therapy. Therapeutic Plasma Exchange (TPE) has been described to be effective in managing various immune-related toxicities, however, the data for using TPE in the setting of acute SOTRs induced by ICIs are limited. Herein, we describe the successful use of TPE in a patient with a history of bilateral lung transplantation who developed an episode of mixed acute cellular and antibody-mediated lung transplant rejection after a single dose of PD-1 inhibitor Pembrolizumab for the treatment of underlying melanoma.

Regional lymph node changes on breast MRI in patients with early-stage breast cancer receiving neoadjuvant chemo-immunotherapy

Abstract Purpose Establishing breast MRI imaging patterns associated with neoadjuvant immunotherapy is needed to monitor response. We analyzed serial breast MRIs in patients receiving neoadjuvant chemo-immunotherapy on the I-SPY2 clinical trial. Methods Patients with stage 2–3 HER2-negative breast cancer were randomized to weekly paclitaxel (control), weekly paclitaxel and pembrolizumab, or weekly paclitaxel, pembrolizumab and intra-tumoral injection of SD-101, a TLR9 agonist. All patients received AC. Regional lymph nodes were retrospectively evaluated on breast MRI at baseline, 3, 12 and 20 weeks by a single blinded radiologist. MRIs were assessed for development of new regional lymphadenopathy, or increase in the longest diameter or cortical thickness of the largest abnormal regional lymph node. Results Between 12/2015 and 4/2021, a total of 43 patients enrolled in the control (n = 16) and paclitaxel + pembrolizumab ± SD-101 (n = 27) arms. 12 of 27 patients (44.4%) receiving chemo-immunotherapy experienced increased lymphadenopathy within the first 12 weeks compared to 1 of 16 patients (6.3%) in the control group (p = 0.014). Most patients with increased lymphadenopathy were in the SD101/pembro arm (n = 10, p = 0.002). Increased lymphadenopathy was observed despite concomitant decrease in breast tumor size at all time points. 11 of 12 patients with increased lymphadenopathy had pathologically negative nodes at surgery. There was no association between lymphadenopathy and lower residual cancer burden or immune-related toxicity. Conclusions The combination of neoadjuvant paclitaxel and pembrolizumab ± SD101 intratumoral injection was associated with early increases in regional lymphadenopathy on MRI despite decreased breast tumor size. Increased lymphadenopathy was not associated with node positive disease at surgery.

Combination of immune checkpoint inhibitors and radiotherapy in locally advanced esophagogastric junction adenocarcinoma: A review.

Esophagogastric adenocarcinoma (EGJ-AC) poses a significant global health burden, characterized by high incidence rates and poor prognosis. Despite advancements in treatment modalities, including surgery, chemotherapy, and radiation therapy (RT), locally advanced EGJ-AC management remains challenging. Various preclinical and clinical studies have provided insights into the synergistic effects of combining immune checkpoint inhibitors (ICIs) with RT, further supporting the combination therapy in EGJ-AC. Immunotherapy, particularly ICIs, has emerged as a promising therapeutic approach in various malignancies, including EGJ-AC. This narrative review aims to critically examine the rationale behind combining ICIs with standard treatment modalities, including RT or chemoradiotherapy, in the preoperative setting for locally advanced EGJ-AC. A comprehensive literature search identified eight phase 2 randomized clinical trials evaluating the safety profile and oncologic outcomes of adding ICI agents to neoadjuvant chemoradiotherapy in this population. The results of enrolled trials show that the combination of ICIs with standard treatment modalities is a promising approach for improving survival and pathological response in patients with locally advanced EGJ-AC. This combination treatment was associated with mostly grade 1-2 immune-related toxicities, indicating its safety and tolerability. There were higher rates of complete or major pathologic responses compared to historical controls. Further studies, including large-scale randomized controlled trials, are needed to address remaining questions regarding the efficacy, safety, and long-term outcomes of combination therapy in this population.

Ophthalmic Immune-Related Adverse Events and Association with Survival: Results From a Real-World Database

PurposeAssessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DesignA retrospective cohort study MethodsData were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. ResultsA cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = 0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). ConclusionsOphthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

1045P The association of human leukocyte antigen variants in immune-related toxicity and efficacy in Chinese lung cancer patients treated with immune checkpoint inhibitors

1045P The association of human leukocyte antigen variants in immune-related toxicity and efficacy in Chinese lung cancer patients treated with immune checkpoint inhibitors

67O Polygenic risk score associations with immune checkpoint inhibitors related endocrine toxicity

67O Polygenic risk score associations with immune checkpoint inhibitors related endocrine toxicity

IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade

Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune related toxicities which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes both augmenting antitumor immune responses and decreasing systemic toxicities. We have recently shown that a doubly recombinant oncolytic myxoma virus which secretes a soluble version of PD1 as well as an IL12 fusion protein (vPD1/IL12) can cause potent regression of disseminated cancers. Here we show that despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL12 still results in systemic, IL12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor-α with tumor necrosis factor receptor-2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL12 mediated toxicities to be alleviated through the use of FDA approved TNF-blockers such as Etanercept.

Sarcopenia and immune-related toxicity in patients with malignant melanoma undergoing immune checkpoint inhibition

Sarcopenia is the generalized loss of muscle strength, mass, and function. The aim was to investigate whether pretherapeutic sarcopenia, as determined by the psoas muscles, affects therapy-mediated toxicity in patients with malignant melanoma undergoing immunotherapy. Measurement of psoas musculature was performed pretherapeutically using computed tomography at the level of the third lumbar vertebra in the axial plane in 75patients between January 2011 and December 2020. Sarcopenia was defined using the psoas muscle index (PMI). Immune-related toxicity was retrospectively assessed. Treatment-related toxicity was recorded in 33of the 75patients (44%). Of these, 16patients (36.2%) experienced dose-limiting severe events (DLT). Pretherapeutic sarcopenia was identified in 25patients (33.3%). Comparative analysis showed that the patients with aDLT had lower PMI values compared with the patient group without aDLT (4.65 ± 1.33 vs.5.79 ± 1.67 cm2m-2, p = 0.015) (odds ratio = 0.60, 95% confidence interval 0.40-0.92, p = 0.02). Pretherapeutic sarcopenia measured based on the psoas muscle is not asignificant predictor of immune-mediated toxicity in patients with malignant melanoma treated with immune checkpoint inhibitors. Patients with DLT have lower values for the psoas muscle parameters PMI compared to the group of patients without DLT.

Arming AAV9 with a Single-Chain Fragment Variable Antibody Against PD-1 for Systemic Glioblastoma Therapy.

Glioblastoma (GBM) is a highly aggressive brain cancer with a low survival rate, prompting the exploration of novel therapeutic strategies. Immune checkpoint inhibitors have shown promise in cancer treatment but are associated with immune-related toxicities and brain penetration. Here, we present a targeted approach using an adeno-associated virus serotype 9 (AAV9) to systemically deliver a single-chain fragment variable antibody against PD-1 (scFv-PD-1) into the tumor microenvironment (TME). Single-cell RNA sequencing analysis revealed robust PD-1 expression in GBM TME, predominantly on T cells. AAV9-scFv-PD-1 expressed and secreted scFv-PD-1, which effectively binds to PD-1. Systemic administration of AAV9-scFv-PD-1 in an immunocompetent GBM mouse model resulted in a robust cytolytic T-cell activation at the tumor site, marked by accumulation of IFN-γ and Granzyme B, leading to a significant reduction in tumor growth. Importantly, AAV9-scFv-PD-1 treatment conferred a survival benefit, highlighting its therapeutic potential. This study demonstrates the feasibility of systemically delivered AAV9-mediated local expression of scFv-PD-1 for targeted immunotherapy in GBM and warrants further investigation for clinical translation.

Cardiovascular toxicities of immune therapies for cancer-a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. This investigator-initiated trial was funded by Merck.

Clinical characteristics and prognosis of pancreatitis associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have shown remarkable efficacy against various cancers in clinical practice. However, ICIs can cause immune checkpoint inhibitor-associated pancreatic injury, often leading to drug withdrawal, and then patients must go to specialized treatment. The patients, their primary tumors are sensitive to ICIs therapy, may experience treatment delays due to such adverse reactions. Therefore, there is a need for systematic clinical researches on immune-related pancreatic toxicity to provide a clinical basis for its prevention and treatment. This study involved the collection of data from patients treated with ICIs and addressed pancreatic injury with preemptive treatment before continuing ICIs therapy. Then, we also statistically analyzed the incidence of pancreatic injury in patients with different courses and combined treatment, and the success rate of rechallenge treatment. The study included 62 patients, with 33.9% (21/62) experiencing varying degrees of pancreatic injury. Patients with pancreatic injury, 10 cases evolved into pancreatitis, representing 47.6% (10/21) in the pancreatic injury subgroup and 16.1% (10/62) of the total patient cohort. Preemptive treatment was administered to 47.6% (10/21) of patients with pancreatitis, the effective rate was 100%. Among these patients, 70% (7/10) underwent successful rechallenge with ICIs. The occurrence of pancreatic injury was positively correlated with the treatment duration (P < 0.05) but showed no significant correlation with combination therapies (P > 0.05). The likelihood of pancreatic injury increased with longer treatment durations with ICIs; no significant association was found between the incidence of ICIs-related pancreatic damage and combination therapies. Preemptive treatment for immune-related pancreatitis is feasible, allowing some patients to successfully undergo rechallenge with ICIs therapy.

Transarterial chemoembolization for renal cell carcinoma patients with liver metastases in the era of immunotherapy: A case series

Treatment for renal cell carcinoma (RCC) has changed rapidly in the past decade with the widespread implementation of immune checkpoint inhibitors (ICIs) as first-line therapy in metastatic disease. The presence of liver metastases is a poor prognostic indicator but also has the potential to be a target for localized therapy. However, there is limited knowledge on the dynamics and long-term effects of combining liver-directed transarterial chemoembolization (TACE) with ICI therapy. We identified four patients with metastatic RCC (mRCC) and liver metastases who were treated concurrently with ICIs and TACE to metastatic liver lesions from our institutional database. We assessed treatment radiological responses and toxicity in this cohort. Liver-directed TACE with concurrent ICI was associated with radiological response or stabilization in all the liver lesions in the four patients in this cohort with a median time to locoregional liver metastasis progression-free survival of 8.3 months (range 6.0–11.1). The concurrent administration of ICI therapy and TACE to liver lesions was well tolerated with no new safety signals and no immune-related toxicities. Combining TACE with ICI in patients with mRCC showed promising response with limited toxicity. Future studies are warranted to clarify treatment timing and validate benefits.

Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart.

Immune-checkpoint inhibitors (ICIs) have revolutionized oncology, with nearly 50% of all patients with cancer eligible for treatment with ICIs. However, patients on ICI therapy are at risk for immune-related toxicities that can affect any organ. Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic Tlymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication. ICI-mediated myocarditis (ICI-myocarditis) is a growing clinical entity given the widespread use of ICIs, its increased clinical recognition and growing use of combination ICI treatment, a well-documented risk factor for ICI-myocarditis. In this Review, we approach ICI-myocarditis from a basic and mechanistic perspective, synthesizing the recent data from both preclinical models and patient samples. We posit that mechanistic understanding of the fundamental biology of immune-checkpoint molecules may yield new insights into disease processes, which will enable improvement in diagnostic and therapeutic approaches. The syndrome of ICI-myocarditis is novel, and our understanding of immune checkpoints in the heart is in its nascency. Yet, investigations into the pathophysiology will inform better patient risk stratification, improved diagnostics and precision-based therapies for patients.

NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer.

LBA3504 Background: The prognostic advantage of early stage deficient-MMR/MSI-High colorectal cancer (CRC) is lost after relapse. Hence, there is a clinical imperative to maximise the chance of cure in early-stage disease. Tumour mutation burden (TMB) is an emerging biomarker for response and clinical benefit to immunotherapy in the advanced setting. NEOPRISM-CRC (Neoadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) is the first multicentre Phase II Trial to determine if neoadjuvant pembrolizumab is efficacious and safe, prospectively stratified to TMB. Methods: The trial population included patients (pts) with operable high-risk stage 2 or stage 3 dMMR/MSI-High CRC. Pts with tumours that were TMB high or medium (≥6 mutations/Mb on FoundationOneCDx test) received 3 cycles of pembrolizumab (200mg every 3 weeks) and underwent surgery within 4-6 weeks of last cycle. Pts with TMB low tumours (≤5 mutations/Mb) underwent surgery 4-6 weeks after 1 cycle of pembrolizumab. The primary end point was pathological complete response rate (pCR). Secondary endpoints included 3-year relapse free survival, overall survival, safety, and health-related quality of life. The trial also incorporated translational endpoints to explore relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumour tissue and microbiome. We required 19 pts with TMB high or medium tumours to detect a pCR after 3 cycles of neoadjuvant pembrolizumab of 33% (minimum of 10%), with one-sided 5% significance level and 80% power (A’Hern single stage). The trial would be considered a success if ³5/19 of those pts achieved pCR. To achieve this number, we aimed to recruit 32 patients in total. Results: The trial opened on 20th July 2022 and 32 pts were rapidly enrolled. The pCR primary endpoint analysis was performed on 1st March 2024. The primary endpoint was exceeded with the pCR in the intent to treat pts (N=32) as well as the pCR in evaluable tumours shown in Table 1. Median TMB was 42 mutations/Mb (4-82). There was only 1 TMB low tumour and no TMB medium tumours. In the TMB high-medium cohort there were 32 evaluable resected tumours as 1 pt had 3 synchronous primaries, and 1 pt did not undergo surgery due to toxicity as well as pt choice. There were no immune-related toxicities &gt;Grade 3. At a median follow-up of 6 months (range 2-15), no pts have had disease recurrence. Conclusions: Neoadjuvant pembrolizumab for early stage deficient-MMR/MSI-High CRC is highly efficacious and safe. Longer follow up is needed to assess relapse free survival and translational biomarker work is ongoing. Clinical trial information: NCT05197322 . [Table: see text]