bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1).
Authors: Winer Ira Seth , Patnaik Amita , Barve Minal A. , Kummar Shivaani , Schenk Erin Lynn , LoRusso Patricia , Yeku Oladapo O. , Fu Siqing , Jahchan Nadine , Myers Matthew , Liang Linda , Deegan Denise , Jackson Lynnae , Li Yunfeng , Reyno Len , Chamberlain Marc Charles
Published: June 2023

2523

Background: This study aimed to characterize the safety of PY159 (an agonist antibody to TREM1 that reprograms immunosuppressive intratumoral myeloid cells) as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors, including subjects refractory to immune checkpoint inhibitors. Methods: Two strata were evaluated, PY159 as a single agent and in combination with pembrolizumab, using an accelerated 3+3 dose escalation study design. Dosing was intravenous once every 3 weeks. Disease assessment by RECIST 1.1 was performed every 6 weeks. The single-agent stratum included 7 dose levels of PY159 (range, 0.01–10 mg/kg). The combination stratum included 4 dose levels of PY159 (range, 0.3–10 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM1 expression by immunohistochemistry. Based on preclinical immunohistochemistry data, HR+ HER2– and triple-negative breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, and gynecologic cancers were studied. Results: Thirty-seven subjects (median age 65 years; range 29–86 years; 22 female and 15 male) with an ECOG PS <2 were enrolled and all but 5 were RECIST-evaluable (3 withdrew consent, 1 sustained a TEAE, and 1 had a DLT, an asymptomatic grade-3 transaminitis). Twenty subjects received single-agent PY159 and 17 received PY159 in combination with pembrolizumab. Four subjects experienced a grade-3 TRAE, 14 a low-grade immune-related reaction, 18 an SAE (related in 2), and 14 an immune-related adverse event (arthralgias). There were no SUSARs. Five subjects sustained high-grade TRAE resulting in discontinuation. TREM1 levels in the tumors ranged from 0 to 15%. Pharmacokinetic parameters were linear beyond the 0.3 mg/kg dose, dose proportional with a half-life of 8–9 days, and unaffected by pembrolizumab. Radiographic response included 2 partial responses (1 each in an ovarian and pancreatic cancer subject) and stable disease in 9 subjects, ranging from 12 to 96+ weeks. Two subjects continue receiving PY159. Conclusions: PY159 was well tolerated, with an acceptable safety profile, as a single agent and in combination with pembrolizumab. A dose for expansion was derived and enrollment of subjects with 7 prespecified cancers is ongoing. Clinical trial information: NCT04682431 .
Peri Cruiser CAR-T: An innovative platform to reduce on-target off-tumor toxicity of CAR-T therapy.
Authors: zhang shuangshuang , Hao Ruidong , Wang Hongye , Yi Qiao yong , Yantao Li , Zhong Yunpeng , Sun Minmin
Published: June 2023

2539

Background: On-target off-tumor toxicity is a significant concern in Chimeric Antigen Receptor (CAR)-T therapies, especially for solid tumors, leading to adverse effects on normal tissues and impacting on treatment efficacy. To address this challenge, a modified form of CAR-T cells named Peri Cruiser CAR-T has been developed by using miRNA technology to knock down three adhesion genes that mediate T cell transendothelial migration to normal tissues, aiming to block the extravasation of CAR-T cells so that the on-target off-tumor toxicity could be prevented without compromising anti-tumor efficacy. In this study, we provided a proof of concept by using the epithelial cell adhesion molecule (EpCAM) as a targeting tumor-associated antigen (TAA). Methods: An miRNA cassette was incorporated into the vectors of anti-human or mouse EpCAM CARs. The knockdown efficiency, endothelial adhesion efficiency, effector functions and memory phenotypes in vitro were evaluated. To determine the toxicity in vivo, the anti-mouse EpCAM CAR-T cells were administered to non-tumor bearing NSG mice, and the body weight and T cell infiltration in normal tissues was evaluated. Anti-tumor efficacy was also evaluated in NSG mice with subcutaneous and metastatic tumor models by anti-human EpCAM CAR-T cells. Results: Our Peri Cruiser CAR-T platform was capable to effectively downregulate the target genes by 10 folds. The knockdown is stable after extended culture and antigen engagement in vitro. This knockdown of targeted genes significantly decreased T cell adhesion to endothelial cells and corresponding ligands, but did not affect T cell activation or effector functions such as cytotoxicity and IFN gamma release. Surprisingly, lowering the levels of these adhesion molecules improved the memory phenotypes of CAR-T cells as indicated by increased portion of CCR7+CD45RO+ cells. In vivo studies showed that conventional EpCAM CAR-T-injected mice experienced severe weight loss and all had to be sacrificed before day 8, the IHC staining of CD3 revealing massive infiltration of T cells in lung, liver, and kidney. However, the incorporation of the miRNA cassette prevented T cell infiltration in normal tissues, reversed the toxicity, and ensured the survival of all mice. The anti-tumor efficacy of these T cells was evaluated in vivo and found to decrease metastasis as effectively as the conventional CAR-T cells in a metastasis model of HCT116-Luc, although there was a slightly but not significantly decreased efficacy in a subcutaneous model of HCT116. Conclusions: The Peri Cruiser CAR-T platform can significantly improve the safety of CAR-T cells without compromising their efficacy to eliminate tumor cells in primary site and metastasis. This technology opens another avenue to safely target a variety of other TAA by CAR-T even when there is the potential of on-target off-tumor toxicity in normal tissues for those antigens.
Selective recognition of over-expressed self-antigens in solid tumors using calibrated CAR-T therapy.
Authors: Haerizadeh Farzad , Jiang Helena , Cooper Laurence
Published: June 2023

2540

Background: CAR-T has shown promise in patients with a subset of solid tumors. Future development depends on identifying CAR-T that differentiate between normal and malignant cells. The PrismCore platform develops CAR-T targeting self-antigens using three principles: 1) identification of targets uniformly expressed on solid tumors, 2) over-expression on the surface of invasive cancers compared to healthy cells, and 3) elevated levels linked to tumor aggressiveness. PrismCore produces CAR-T for treating multiple solid tumor types by calibrating T-cell activity against self-antigens only when present at elevated densities. Methods: PrismCore generates CAR-T by combining computational biology with empirical observations to target over-expressed self-antigens. Proto-libraries of CARs are created using synthetic single-domain antibodies and structural/signaling components. Bio-screening is performed using combinatorial libraries generated through computational simulation. Lead CAR-T are identified through iterative in vitro and in vivo testing and evaluated for safety in non-human primates (NHP). Results: PrismCore platform has identified engineered T cells against several self-antigens, with the first CAR-T, termed B4t2-001, advanced to clinical testing against the target BT-001. Libraries (1E10 to 1E11) of camelid antibodies were designed, synthesized, and assessed. Selected antibody variants subsets were combinatorially assembled into CAR-Ts and rigorously screened against gradient of BT-001. Six candidates were advanced to further testing in mice to evaluate anti-tumor effect and sustained in vivo biological activity. B4t2-001 was evaluated in NHP that express basal levels of BT-001. No toxicity observed despite measurable circulating CAR-T and in vitro activity to NHP BT-001 when at high density. The turnaround from target selection to B4t2-001 for clinical evaluation was six months. Conclusions: We report pre-clinical data for B4t2-001 that safely and effectively targets BT-001 when overexpressed on tumors. This is a novel target for T-cell therapy and is at elevated levels on multiple different types of solid tumors. BT-001 participates in pathobiology, tumor invasion as well as metastasis, and level of expression inversely correlates with overall survival. B4t2-001 demonstrated target density-dependent response, potency, durability of effect and safety in preclinical models and is undergoing phase I clinical evaluation (NCT05621486) in patients with different types of solid tumors. [Table: see text]
Effect of the killing style of individual CAR T cells on the clinicopathological behavior of therapeutic products in the clinic.
Authors: Gad Ahmed Z , Morris Jessica S , Godret-Miertschin Lea , Montalvo Melisa J , Berger Harrison , Brock Rebecca M , Fousek Kristen , Srinivasan Madhuwanti , Saeedi Arash , Levental Kandice , Mamonkin Maksim , Carisey Alexandre , Varadarajan Navin , Hegde Meenakshi , Joseph Sujith , Levental Ilya , Mukherjee Malini , Ahmed Nabil
Published: June 2023

2548

Background: CAR T cell products that signal through CD28 and 41BB are highly effective against B lineage leukemia, despite exhibiting distinct efficacy and toxicity profiles in patients. Specifically, CD28 has been linked to higher upfront lytic activity and toxicity, while 41BB induces longer CAR T cell persistence and more durable progression free survival. We reasoned that the killing style of individual CAR T cells can explain the clinicopathological behavior of CAR T cell products in the clinic. Methods: We studied the cellular kinetics of CD28 and 41BB signaling CD19 CAR T cell products approved in the clinic, their single cell killing behavior in high throughput, the molecular composition of the lipid rafts inside the CAR immune synapse (CARIS) they form with their target cells, and their CARIS mechanical properties, then corroborated these findings in one kinetic model to explain their distinct clinicopathological behavior in the clinic. Results: We discovered that tumor encounter polarizes CD28 CAR T cell products to a predominance of more differentiated CD8 effectors that rely on short-lived highly lethal synapses with tumor cells. CD28 CAR T cell mediated synapses are characterized by fast mechanical buildup and resolution and brisk shuttling of CAR and other associated molecules into the CARIS and rapid polarization of the killing machinery in a manner that supports a mastery of serial killing mediated by perforin and granzymes. In contrast, 41BB responds to tumor stimulation by a Th2 -polarizing cytokine milieu that robustly expands a balanced CD4/CD8 population of effectors preserving a central memory phenotype. 41BB CAR T cells engage in lengthier synapses characterized by slower accumulation of CAR molecules in a mechanically tonic CARIS and rather collaborative yet lengthy Fas ligand-mediated killing process. Conclusions: We show here that CAR T cell signaling domains mediate distinct killing dynamics that can explain their behavior in patients. By understanding and potentially modulating these dynamics, the CAR T cell functionality and toxicity can be rationally optimized.
Preclinical evaluation of targeting PRAME with TCR mimic CAR T cells in AML.
Authors: Kirkey Danielle , Robinson Leila , Hylkema Tiffany , Loeb Anisha , Castro Sommer , Tang Thao , Ries Rhonda E , McKay Cyd , Root Christina , Pardo Laura , Loeb Keith , Le Quy , Meshinchi Soheil
Published: June 2023

2553

Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment, but has had limited success against AML in part due to overlap of cell surface antigens expressed in AML and normal hematopoietic cells. To identify AML-restricted targets, we interrogated the transcriptome from over 3000 AML patients and found PRAME (Preferentially Expressed Antigen in Melanoma), an intracellular protein, to be a highly expressed AML-restricted target. Using a novel approach to target intracellular antigens, we developed a PRAME CAR T cell using a TCR mimic (mTCR) antibody, which recognizes the PRAME peptide/HLA-A2 complex on the tumor cell surface. To conduct final IND-enabling studies, we generated an in vivo patient derived xenograft (PDX) model to treat with PRAME mTCRCAR T cells. Here we demonstrate the in vivo activity of PRAME mTCRCAR T cells against a PDX AML model. Methods: We used the VL and VH sequences from the PRAME TCR mimic antibody (Pr20) to construct the single chain fragment variable domain into the 41-BB/CD3ζ CAR vector. The PDX model was derived from a PRAME+/HLA-A2+ pediatric patient with AML. PDX cells were transduced with ffluciferase for noninvasive bioluminescent IVIS imaging to monitor leukemic progression. PDX leukemia-bearing mice were treated with unmodified T-cells or PRAME mTCRCAR T cells at 5x106 cells (1:1 CD4:CD8) per mouse 1 week after leukemia injection. Leukemia burden was measured by IVIS imaging and peripheral blood analysis. Results: Treatment with PRAME mTCRCAR T cells led to eradication of leukemia with all mice alive >100 days post-treatment, while control mice (unmodified T cells) had disease progression at Day 50 (p=0.001). Average leukemia burden in the control cohort was 3.5% at week 6 and 41.75% at week 11, while no leukemia was detected following CAR T cell treatment. In addition, the control arm had a marked expansion of leukemia with a 7.75 and 429.6 fold increase in radiance by IVIS at 6 and 11 weeks post-treatment. No significant increase in radiance was seen in the PRAME mTCRCAR T cell treated group. Human T cells (CD45+/CD3+) were detectable in the peripheral blood at Day 7 and 14 post-treatment in both the unmodified and CAR T cell treated groups. Conclusions: We demonstrate the therapeutic potential of targeting PRAME with mTCRCAR T cells in AML. We show potent efficacy with eradication of leukemia in PDX-bearing mice following treatment with PRAME mTCRCAR T cells resulting in prolonged survival. These results provide a novel approach to target PRAME with CAR T cells and provide compelling data to evaluate PRAME mTCRCAR T cells for use in clinical trials against AML. [Table: see text]
The exploratory case-control study on prediction of immune checkpoint inhibitor-induced thyroiditis by human leukocyte antigen types.
Authors: Natori Yutaka , Sasaki Eisaku , Suga Junko , Kimura-Tsuchiya Reiko , Tokuda Emi , Saji Shigehira
Published: June 2023

2558

Background: Given the function of human leukocyte antigen (HLA) in immunity, variation of the HLA type could affect the development of immune-related adverse events (irAEs) that is induced by immune checkpoint inhibitors (ICIs). In this study, we examined whether HLA types of cancer patients could be a marker for the development of irAE thyroiditis. Methods: In the present case-control study, we randomly selected 20 cancer patients who received ICIs and developed thyroiditis (irAE thyroiditis group) and 51 who did not develop thyroiditis (No irAE thyroiditis group). The 51 patients were subdivided into 31 who did not develop any irAEs (No irAEs group) and 20 who developed irAEs other than thyroiditis (irAEs other than thyroiditis group). HLA types were classified at the amino acid sequence level (Field 2 resolution). Frequency of the HLA types of each group was compared. Results: There was no significant difference in HLA type prevalence, comparing the irAE thyroiditis group and the No irAE thyroiditis group. When comparing the irAE thyroiditis group with the No irAEs group, the irAE thyroiditis group had significantly higher HLA-X, HLA-Y, and HLA-Z (Tentative names are used here, and actual HLA types will be announced at the time of publication). This result suggested that irAEs other than thyroiditis in the control group could be noise. HLA-X had a specificity of 96.8% for the development of irAE thyroiditis. HLA-Y had a sensitivity of 80.0%. Patients carrying both HLA-X and HLA-Y had the highest specificity of 100.0%. There was a significant difference in frequency of HLA-Y between irAEs other than the thyroiditis group and the No irAEs group. HLA-Y may be a universal marker for any irAEs. On the other hand, HLA-X is a specific marker for thyroid irAE. The median time of onset of irAE thyroiditis in all patients was 72 days after ICI administration. Patients with both HLA-X and HLA-Y tended to have an earlier onset with a median onset time of 53 days. Conclusions: We found an association between specific HLA types and the development of irAE thyroiditis. The present study indicates that HLA types could be a predictive marker for the development of irAE thyroiditis.
The prognostic ability of immune scoring system Immunoscore in patients with localized colon cancer: A systematic review and meta-analysis.
Authors: Padayao John Lois , Dy Carlos
Published: June 2023

2565

Background: Assessment of tumor recurrence risk as well as prognosis in resectable colon cancer are still mainly based on the histopathological criteria of tumor invasion reflected in the TNM classification. Robust data in colorectal tumor research show the value of tumor microenvironment and tumor‐infiltrating lymphocytes (TILs) as novel parameters to predict recurrence and survival. The utility of the derived tumor Immunoscore via digital pathology is now being promoted to refine the prognosis of early colon cancer patients together with the TNM staging to guide treatment decisions, but is not yet a recommendation in international consensus guidelines. This study assessed the prognostic value of this diagnostic tool in predicting clinical outcomes. Methods: A systematic literature search using PubMed, Embase, and Cochrane CENTRAL Library was conducted to identify observational or randomized controlled studies from January 2008 and December 2022 according to pre- specified inclusion and exclusion criteria which examined the relationship between Immunoscore and long-term prognosis (overall survival and disease free survival) in patients with localized colon cancer. Hazard ratios with 95% confidence interval for overall survival (OS) and disease-free survival (DFS) were extracted. Pooled estimates of the prognostic ability of Immunoscore were obtained using bi-variate random effects model. Statistical heterogeneity between studies was evaluated with I2 statistics and explored through sensitivity analysis. Results: A total of 5,718 patients from 11 studies were included in the meta-analysis. Moderate heterogeneity between studies for both DFS (I2= 27%) and OS (I2= 33%) was seen. The pooled analysis indicated that compared to those with high Immunoscore, colon cancer patients with low Immunoscore were associated with shorter disease-free survival (HR 1.75, 95% CI 1.53 - 2.49) and overall survival (HR 1.87 95% CI 1.45 – 2.13). In the subgroup analyses, this association was consistent across geographic regions and maximum time of follow up. Conclusions: A low Immunoscore was significantly associated with poorer clinical outcomes in terms of disease-free survival and overall survival. The use of Immunoscore provides valuable estimate of the risk of recurrence in patients with early colon cancer and has the potential to greatly affect treatment decisions in conjunction with the existing risk assessment system.
Uliledlimab and toripalimab combination therapy in treatment naive advanced NSCLC: Phase 1b/2 clinical trial results using CD73 as a potential predictive biomarker.
Authors: Zhou Qing , Wu Lin , Jiang Bo , Du Yingying , Wang Buhai , Hu Xiaohua , He Yong , Zhao Mingfang , Yao Yu , Cui Jiuwei , Dong Xiaorong , Zhang Haibo , Ma Rui , Wang Huijuan , Zhang Jian , Xia Jinjing , Zhang Yanni , Hayslip John W. , Zhu Andrew X. , Wu Yi-Long
Published: June 2023

2570

Background: CD73 is a rate-limiting enzyme in adenosine pathway promoting immune suppression in tumor microenvironment. The role of CD73 as a novel target in cancer immune therapy is further supported by correlation between its high expression in tumors and poor prognosis in cancer pts. Here we evaluate safety and efficacy of uliledlimab, a differentiated CD73 antibody, in combination with toripalimab, a PD-1 antibody, in treatment naive NSCLC pts. In particular, we investigate the correlation between clinical response and tumor CD73 expression to assess its value as a potential predictive biomarker, following a previous study where a correlation was indicated (Robert F, et al. ASCO 2021). Methods: Pts with treatment naïve advanced NSCLC (EGFR/ALK wild type) were enrolled in a dose-expansion cohort and received uliledlimab (20mg/kg or 30mg/kg Q3W) in combination with toripalimab 240mg Q3W. Safety, the primary endpoint, and clinical efficacy including ORR, determined by iRECIST, were evaluated. Baseline CD73 and PD-L1 expression in tumor specimens were measured by IHC. The cut-off value for CD73High expression was assessed by ROC analysis for correlation with ORR. Results: As of 12/2/22, 66 pts were enrolled (median age 62.5 years, ECOG PS 0 40.6%, male 84.8% and never smokers 22.7%) and received at least one dose. Treatment-related adverse events (TRAEs) occurred in 86.4% of pts (Gr≥3, 15.2%) with no grade 5 TRAE. One patient was discontinued due to TRAE (1.5%). Efficacy was analyzed in 48 pts who were enrolled at least 90 days prior to data cut-off, allowing for two assessments. Baseline PD-L1 and CD73 expression was available in 45 pts. 40% of tumor or immune cells with ≥1+ staining intensity by IHC was determined as a preliminary cut-off for CD73High (the area under ROC curve =0.72, p = 0.02). While ORR and DCR were 31.3% (15/48) and 79.2% (38/48) respectively in all pts, ORR appeared higher in CD73High pts (50%, 9/18) and much lower in CD73Low pts (14.8%, 4/27). Highest ORR was found in a cohort with CD73High and PD-L1 TPS≥1% (57.1%, 8/14). Conclusions: Uliledlimab and toripalimab combination therapy was well-tolerated in treatment naïve advanced NSCLC pts. Clinical response of the therapy seems to correlate with high tumor CD73 expression, indicating a potential value of CD73 as a predictive biomarker. The study warrants a biomarker-guided randomized clinical trial that is currently in preparation. Clinical trial information: NCT04322006 .
Enhancing STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy.
Authors: Zhou Xingwu , Sun Xiaoqi , Gong Wang , Lei Yu Leo , Moon James
Published: June 2023

2571

Background: Activating the innate immune pathway of stimulator of interferon genes (STING) can elicit potent anti-tumor immunity via the production of type-I interferons (IFN-I). However, cyclic-dinucleotide (CDN) STING agonists have undesirable pharmacological properties. Most CDNs in clinical development are administered intratumorally, thus precluding their applications in treating metastasis, hematologic malignancies, and hard-to-reach solid tumors. Here, we report the development of a new nanoparticle system for the systemic delivery of CDN STING agonists with potent efficacy, favorable pharmaceutical properties, and acceptable safety profiles. Methods: Nutritional metal ions play crucial roles in modulating immune pathways, which could potentially be used for enhancing STING activation. We screened different metal ions and found that manganese ion (Mn2+) achieved strong synergy with CDN STING agonists for inducing IFN-I production. We further developed a new nanoparticle system for co-delivery of Mn2+ and CDN for systemic cancer immunotherapy. Results: Mn2+ induced up to 77-fold enhancement in CDN-mediated STING activation. Mixing CDNs with Mn2+ resulted in the self-assembly of nanocrystals, and the lipid layer coating led to uniform nanoparticles. The resulting STING-activating CDN-Mn nanoparticle (SNP) given intravenously elicited IFN-I responses, attenuated the suppressive functions of myeloid cells, remodeled the immunosuppressive tumor microenvironment, and expanded CD8+ T cells for sustained tumor control. Intravenous SNP therapy resulted in robust anti-tumor efficacy in multiple murine tumor models, including a genetically engineered mouse model of MMTV-PyMT triple-negative breast cancer. We have also demonstrated the robust anti-tumor efficacy of SNP against VX2 head and neck squamous cell carcinomas (HNSCC) in New Zealand white rabbits. Mechanistically, the efficacy of intravenous SNP therapy was dependent on the host STING expression but independent of the tumor STING expression. In addition, the anti-tumor efficacy of SNP was decreased in mice lacking Ifnar1 or Ifngr1 expression in the B16F10 melanoma model, showing the crucial effects of IFN-I and IFN-II responses. Lastly, SNP was effectively uptaken by human PBMCs and elicited IFN-I responses when injected into fresh human tumor biopsies derived from HNSCC patients. Conclusions: SNP empowers highly effective systemic cancer immunotherapy via nanotechnology. It also underscores the potential of utilizing metal ions for immune-mediated disease treatment.
T cell engager (TCE) score in patients treated with bispecific CD3 TCE in phase I clinical trials.
Authors: Herbel Noé , Goldschmidt Vincent , Michot Jean-Marie , Laparra Ariane , Geraud Arthur , Ouali Kaissa , Danlos Francois-Xavier , Vuagnat Perrine , Bernard-Tessier Alice , Gazzah Anas , Bahleda Rastilav , Hollebecque Antoine , Marabelle Aurelien , Postel-Vinay Sophie , Loriot Yohann , Massard Christophe , Ribrag Vincent , Ponce Aix Santiago , Champiat Stephane , Baldini Capucine
Published: June 2023

2573

Background: Immune prognostic scores, such as the Gustave Roussy Immune (GRIM) score have been investigated in patients (pts) treated with immune check-point blockers. We aimed to determine whether we could improve the selection of pts that could benefit from new immunotherapies such as bispecific CD3 T cell engagers (TCE) antibodies in pts treated in phase I clinical trials (CT), by building a new prognostic score. Methods: All patients treated with bispecific CD3 TCE in phase I CT from July 2018 to February 2023 at the Drug Development Department at Gustave Roussy were enrolled in the study. Univariate and multivariate analyses (UVA and MVA) were conducted on demographic, clinical and biological data to assess their prognostic value on progression free survival (PFS). MVA results were used to build a new prognostic score (TCE score). This score was then validated on overall survival (0S). The predictive ability (on PFS and OS) of the TCE score was assessed using Harrell’s C index. It was compared with the GRIM and Royal Marsden Hospital (RMH) scores predictive ability on PFS and OS. Results: A total of 67 patients (47 men, 20 women) with metastatic solid cancer or advanced hematological cancer were included. Median age was 62 years old. The most represented tumor types were prostate cancer (33%), lymphoma (25%) and small cell lung carcinoma (24%). UVA on PFS showed that elevated C-reactive protein (CRP) (HR: 2,36; 95%CI: 1,35-4,16; p = 2.10-3) and lactate dehydrogenase (LDH) (HR: 3,00; 95%CI: 1,63-5,53; p = 2.10-4) were associated with a worst PFS. In MVA, LDH (HR: 2,49; 95% CI: 1,30-4,74, p = 1.10-4) and CRP levels (HR: 1,92; 95% CI: 1,1-3,46; p = 1.10-4) were independent negative prognostic factors for PFS. The TCE score was based on MVA results (CRP>10g/l: +1; LDH > 250U/l: +1). It showed that pts with a high score (1-2) had a shorter PFS (median PFS: 2,8 months) and OS (median OS: 9,9 months) than low score (0) pts (median PFS: 5,8 months; median OS: not reached). TCE score’s Harrell’s C index for PFS was 0,63 and 0,64 for OS. For GRIM and RMH scores, Harrell’s C index for PFS were respectively 0,60 and 0,55. For OS it was respectively 0,58 and 0,53. Conclusions: To select patients for Bispecific CD3 TCE phase I CT, we built a new prognostic score, based on LDH and CRP levels, that can be used as prognostic of PFS and OS. TCE score is more reliable than GRIM and RMH scores to prognose PFS and OS.
Use of proteomimetic polymers for delivery of tumor antigens and adjuvants through formation of stable electrostatic complexes with small molecule STING agonists.
Authors: Wang Max Mu , Gattis Brayley , Choi Mi Ran , Zhang Bin , Gianneschi Nathan
Published: June 2023

2583

Background: Utilizing tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, significant challenges remain in delivering subunit vaccine components to elicit antitumor immune responses. To overcome these, we developed rationally designed cancer vaccines using a new nanoplatform called the Protein-Like Polymer (PLP) with unique characteristics that allow for sustained delivery of tumor antigens in conjunction with immunomodulatory compounds. Methods: PLPs containing antigens were synthesized via ring-opening metathesis polymerization (ROMP) and characterized using HPLC, LC-MS, NMR, and GPC. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide linkage), DPs, and inclusion of PEG side chains. In vitro assays using gp100-specific T Cells were conducted with fluorescently labeled and non-labeled polymers. In vivo experiments were done using B16 murine melanoma transplanted tumor models. Ability of PLPs to co-deliver immunomodulatory compounds was tested using a small molecule STING agonist 2’3’ cGAMP. Results: Conjugating antigens to the polymer backbone using a cleavable disulfide linkage, designed to be reduced intracellularly, resulted in the best subcellular localization and immune activation (higher levels of immune cell proliferation, cytokine production, and expression of activation markers). Incorporating a diluent amount of PEG side chains increased resistance to enzymatic degradation while improving bioactivity and cell uptake. In vivo studies using PLPs conjugated with melanoma-associated antigen gp100 showed the reductions in tumor size with increased immune cell proliferation and activation in a B16 melanoma model. Additionally, increasing the degree of polymerization, and therefore the density of antigen side chains per unit polymer, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING agonists electrostatically coupled to PLPs showed significantly smaller tumors vs no-treatment at day 14 (0.038g vs 0.76g; p <0.0001) and allowed for subcutaneous administration of the small molecule, which normally must be injected intratumorally. Conclusions: Our work demonstrates the potential of PLPs to overcome inherent difficulties associated with developing cancer vaccines. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.
Patient-derived skin MicroOrganoSpheres and clinical response to immunotherapy.
Authors: Chakraborty Rikhia , Fagan-Solis Katerina , DeVilla Jessica , Recaldin Timothy , Bscheider Michael , Gjorevski Nikolche , Fullerton Aaron , Prell Rodney , Khan Zia , Wang Zhaohui , Ding Shengli , Glass Carolyn , Jeck William , McCall Shannon J. , Beasley Georgia , Mohindra Rajat , Hsu Shiaowen David , Chandler G Scott , Shen Xiling , Roth Adrian B ,   ASCO Authors' Group
Published: June 2023

2588

Background: Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Methods: Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOS), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Results: Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients. Conclusions: This is the first study to date demonstrating the application of a patient-derived immune competent skin model deployable for assessing ICI efficacy and toxicity response. Matched tumor skin MOS from the same patients recapitulated the clinically observed association between ICI efficacy and toxicity and may provide key indicators for prospective irAE-predicting clinical trials.
Retrospective analysis on association of ABO blood type and immune checkpoint inhibitor response.
Authors: Batra Akshee , Singh Rohit , Schuetz Samantha R , Gandler Helen , Devine Derek , Barker Jacob , Rehman Hibba tul , Ahmed Shahid Sattar
Published: June 2023

2596

Background: The presence or lack of a collection of antigenic cell surface markers on red blood cells makes up the ABO blood groups that contribute to various immunogenic neoantigens. Variations in the T-cell diversity and HLA haplotype with different blood types might affect a patient's response to Immune checkpoint inhibitors (ICIs). However, the association between the ABO blood type and ICIs is not well studied. Methods: We did a retrospective observational study to investigate the influence of ABO blood groups on patients receiving ICIs at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs as first-line therapy between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, type and metastasis. We looked at overall survival and the occurrence of immune-related adverse events (irAEs) in different blood type subgroups and calculated relative risks. Results: A total of 288 cases were identified, out of which 169 had documented blood type, including 75 with A, 19 with B, 72 with O and 3 with AB blood type. The mean age was 63.71 years (Standard deviation (SD): 11.52), 58.6% were males, and ethnicity was 94.7% White, 1.2% Asian and 0.6% Hispanic. Lung cancer was most commonly identified at 41%, and 60% of total cancers were stage 4. The median ECOG status was 1 and the Charlson comorbidity index was 6. 36% of cases developed irAEs, whereas mortality was 39% during the study period. The relative risk of irAEs with blood type A and B compared to O was 0.89 and 0.83, respectively but wasn't statistically significant. The relative risk of irAEs of AB compared to O blood type was statistically significant at 2.63 (CI: 1.95-3.54). The relative risk of death in A and B blood types compared to O wasn't statistically significant. No patients in the AB blood group died. Conclusions: Clinically significant association wasn't found between different blood types and irAEs or mortality except for the increased risk of irAEs with AB compared to O. With the rapidly growing use of ICIs, prospective trials are needed to better understand the true risk of developing irAEs in patients with AB blood type. [Table: see text]
A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors.
Authors: Hamid Omid , Gutierrez Martin , Mehmi Inderjit , Dudzisz-Sledz Monika , Hoyle Paul Edward , Wei Wendy , Powderly John D.
Published: June 2023

2599

Background: In cancer treatment (tx), loss of T-cell function is associated with progressive expression of checkpoint (CP) molecules, and resistance or relapse following PD-(L)1 inhibitor therapy is a high unmet need. LAG-3 and TIM-3 are key CP pathways implicated in resistance to PD-1 inhibitors and have shown synergistic effects upon triple inhibition with PD-1 in a murine model. This open-label, nonrandomized phase 1/2 study (NCT04370704) aims to determine optimal doses and preliminary safety and efficacy for the monoclonal antibody combinations of INCAGN02385, INCAGN02390, and retifanlimab. Here we report initial safety and efficacy results. Methods: Study consists of 4 parts in phase 1 and 2 expansion cohorts in phase 2. In phase 1, parts 1 and 2 determined safety of INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W and INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W + retifanlimab 500 mg Q4W, respectively; parts 3 and 4 will test additional dosing schedules. Pts enrolled had previously treated (including PD-[L]1) locally advanced unresectable or metastatic solid tumors, with no prior LAG-3– or TIM-3–directed therapy. Results: As of June 28, 2021, 21 pts were enrolled in parts 1 (n=10) and 2 (n=11); 62% of pts were <65 years and 38% were male. Pts had median 3 (range 1-9) prior lines of therapy, including prior anti–PD-(L)1 (part 1, 8 pts; part 2, 11 pts); pt tumor types are listed. Nineteen pts discontinued tx, 1 due to toxicity. Nine pts in part 1 and 10 pts in part 2 had tx-emergent adverse events (TEAEs), most commonly anemia and diarrhea (each 30%) in part 1 and anemia (36%) in part 2 (all tx-unrelated). Serious tx-related TEAEs occurred in 1 pt in part 1 (grade [G] 3 vasculitis) and 1 pt in part 2 (G3 myocarditis and pericardial effusion). Most common G≥3 TEAE was G3 anemia (part 1, 2 pts; part 2, 3 pts); 1 pt in part 1 had a G5 TEAE of sepsis unrelated to tx, with COVID-19 infection. In part 2, 1 pt had an infusion-related reaction, and 1 pt had immune-related TEAEs of pericardial effusion and myocarditis (both G3 and tx-related), which resolved after steroid therapy and tx discontinuation. Best overall response in part 1 was stable disease, and in part 2 was a confirmed and durable partial response in 1 pt with CP therapy–refractory melanoma. Conclusions: Doublet anti–LAG-3 + anti–TIM-3 and triplet anti–LAG-3 + anti–TIM-3 + retifanlimab regimens in the study were generally well tolerated in heavily pretreated pts, with a safety profile consistent with that of CP monotherapy and no novel toxicities. Optimal doses of both combinations are to be further evaluated in the ongoing study in first-line tx of melanoma. Clinical trial information: NCT04370704 . [Table: see text]
A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.
Authors: Tan David Shao Peng , Ng Matthew C.H. , Subbiah Vivek , Messersmith Wells A. , Strickler John H , diermayr veronica , Cometa Julienne , Blanchard Stephanie , Nellore Ranjani , Pendharkar Vishal , Gan Bong Hwa , Rozaini Nurul Nazihah , Koh Claudia , Sarma Suman , Poh Huay Mei , Lezhava Alexander , SRIRANGAM PRATIVADIBHAYANKARAM VENKATESHAN
Published: June 2023

2601

Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or <1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab & pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .
The impact of renin-angiotensin-aldosterone system inhibitors on immune checkpoint inhibitor-associated adverse cardiovascular events.
Authors: Chiang Cho Hung , Chiang Cho Han , HSIA YUANPING , Chiang Cho Hsien , Shiah Her-Shyong
Published: June 2023

2605

Background: Immune checkpoint inhibitors (ICIs) are associated with adverse cardiovascular events that impair patient outcomes. Previous observational studies showed that renin-angiotensin-aldosterone system inhibitors (RAASi) may mitigate the cardiotoxicity associated with chemotherapeutic agents. However, the effects of RAASi on ICI-associated adverse cardiovascular events are unknown. Methods: We conducted a 1:1 propensity score-matched cohort study involving ICI-treated patients at two tertiary referral centers in Taiwan. The propensity score matching model includes age, sex, hypertension, diabetes mellitus, chronic kidney disease, Eastern Cooperative Oncology Group (ECOG) Performance Scale, cancer stage, and cancer type. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of myocardial infarction (MI), ischemic stroke, peripheral arterial occlusive disease (PAOD), pulmonary embolism (PE), deep venous thrombosis (DVT), heart failure, pericardial disease, myocarditis, and cardiac arrhythmias. The secondary outcomes were arterial thrombotic events (MI, ischemic stroke, PAOD) and venous thrombotic events (PE and DVT). Results: We identified 684 patients eligible for inclusion, from which 164 patients who received RAASi were matched to patients who did not receive RAASi. Over a median follow-up of 9.1 months, the incidence rate of MACE for RAASi and non-RAASi recipients was 6.5 and 13.9 per 100 patient-years, respectively, resulting in an incidence rate ratio of 0.47 [95% CI: 0.21–1.00] (p = 0.038). In a multivariate Cox proportional hazard model adjusting for cancer therapy, RAASi recipients had an approximately 60% reduction in the risk for MACE (HR, 0.37 [95% CI: 0.16-0.86], p = 0.021). In the secondary analysis, RAASi were associated with a reduction in venous thrombotic events (HR, 0.11 [95% CI: 0.02-0.63], p = 0.013), but not for arterial thrombotic events (HR, 0.47 [95% CI: 0.06-3.38], p = 0.45). Conclusions: In patients receiving ICI therapy, the use of RAASi is associated with a decreased cardiovascular risk, particularly for venous thrombotic events. [Table: see text]
The controversial abscopal effect: A single-center experience about the combination of stereotactic radiotherapy with pembrolizumab in patients with metastatic dMMR/MSI-H colorectal cancer.
Authors: Gandini Annalice , Martelli Valentino , Belgioia Liliana , Puglisi Silvia , Cremante Malvina , Murianni Veronica , Damassi Alessandra , Ricciotti Ilaria , Pirrone Chiara , Catalano Fabio , Grassi Massimiliano , Pessino Anna Maria , Pastorino Alessandro , Sciallero Stefania , Puccini Alberto , Sobrero Alberto F.
Published: June 2023

2608

Background: Colorectal cancer (CRC) patients with mismatch repair system deficiency (dMMR/MSI-H) have shown impressive responses to immune checkpoint inhibitors in any lines of treatment. However, almost 30% of these patients are primary refractory and another 30% develop secondary resistance. Thus, many treatment combinations are being pursued to overcome resistance. One of the proposed strategies is the addition of radiotherapy to immunotherapy based on the potential abscopal effect and its consequent on-target and off-target activity. Methods: Between November 2019 and April 2021, we conducted a prospective interventional single-institution study to assess the feasibility, disease control and safety of the combination of pembrolizumab with stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive dMMR CRC patients. SABR was administered in combination within the second or third cycle of Pembrolizumab 200 mg infused every 21 days. SABR was delivered on one or more targetable metastases with the ablative dose of 15 Gy in the first fraction followed by a second fraction of 5 Gy. Results: Fourteen patients were enrolled and 11 received radiotherapy in combination with Pembrolizumab as per protocol. Three patients who started Pembrolizumab never received radiotherapy due to deterioration of their general conditions, leading to death within two months. Two out of these three patients were BRAFV600E mutated. Five patients (35.7%) received Pembrolizumab as first line, 6 (43%) as second line and 3 (21%) as third or later lines. Six out of 14 patients (42.9%) harboured BRAFV600E mutation, 2 out of 14 (14.3%) RAS mutation and the others were RAS/BRAF wild type. Objective response was observed in 4 out of 14 patients (29%) and disease control was achieved in 7/14 patients (50%). Among these, six patients (42%) achieved a disease control lasting more than 15 months. This regimen caused substantial toxicity, mainly linked to SABR. Any grade TRAEs occurred in 50% of patients, with one patient with G1 event, three patients with G2 events, and two patients with G3 events (pneumonia, bowel perforation); no treatment-related deaths were observed. Conclusions: These data do not show hint of added efficacy of Pembrolizumab by SART in unresectable dMMR/MSI-H mCRC.