tbuckley/cabot-search huggingface dataset:
Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.
Authors: Junli Xue, Yan Zhang, Xudong Hu, Wei Zhao, Yuping Sun, Qun Li, Xiaoying Jin, Liqiong Xue, Xiaoxiao Ge, Fengjuan Lin, Wenbo Tang, Jiuli Zhou, Ye Guo
Journal: Journal of Clinical Oncology (2024)

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .
Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.
Authors: Changhua Ji, Bing Kuang, Bernard S. Buetow, Allison Vitsky, Yuanming Xu, Diane Matsumoto, Eugenia Kraynov, Javier Chaparro-Riggers
Journal: Journal of Clinical Oncology (2024)

e14568 Background: Interleukin (IL)-15 is a potent cytokine that enhances the proliferation and effector functions of IL-2Rβ/γ-expressing lymphocytes, such as NK cells and T cell subtypes (CD8+, CD4+, gd, and NKT). PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. PD-1 is expressed on tumor-infiltrating T cells at relatively high levels. PF-07209960 has reduced activity on PD-1-negative NK cells and enhanced activity on PD-1-expressing intratumoral CD8+ T cells, therefore is expected to have improved therapeutic window. Methods: The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a two-dose PKPD (0.01 – 0.3 mg/kg/dose) study and in a three-dose (SC route) GLP toxicity study (0.1 – 3 mg/kg/dose). Results: PF-07209960 showed dose-dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. The expansion of T cells and NK cells in peripheral blood peaked around Day 8 and waned to near baseline levels by Day 15. Release of cytokines IL-6, IFNɣ, and IL-10 were detected, which peaked at 72 hours postdose. All animals at 3 mg/kg/dose were euthanized in a moribund condition on Day 4 of the dosing phase, coincident with the peak of cytokine release. Four out of six monkeys administered 1 mg/kg were euthanized between Day 6 and Day 16 due to thrombocytopenia, bleeding, and poor physical condition. Microscopic evaluations revealed generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively. Conclusions: PF-07209960 demonstrated dose-dependent exposure and robust PD (T cell and NK cell subsets expansion and cytokine release) in cynomolgus monkeys, with well-characterized safety profile. In summary, the results of the present study support Phase I clinical evaluation of PF-07209960 in cancer patients.
Risk stratification for immune effector cell-associated neurotoxicity syndrome in patients receiving chimeric antigen receptor T cell therapy.
Authors: Nathaniel Chishinga, Martha Tendai Mapalo, Charles Douglas Bodine
Journal: Journal of Clinical Oncology (2024)

e14534 Background: Chimeric Antigen Receptor-T (CAR-T) cell therapy is a novel immunotherapy that has successfully been used to treat hematological cancers. However, CAR-T cell therapy has significant neurotoxic adverse effects including immune effector cell-associated neurotoxicity syndrome (ICANS). There is limited data that stratifies patients undergoing CAR-T cell therapy that are at increased risk of ICANS. We therefore investigated characteristics among patients receiving CAR-T cell therapy associated with increased risk of ICANS. Methods: We used ICD-10 codes to query the National Inpatient Sample database from the year 2016 to 2020 to identify patients receiving CAR-T cell therapy, aged 18 years and older. We used logistic regression models with random-effects to adjust for age, gender, race and chronic comorbidities at individual-level and clustering at hospital-level and obtained adjusted odds ratios (aORs) and 95% confidence intervals of factors associated with ICANS among patients receiving CAR-T cell therapy. Results: Of 467 patients receiving CAR-T cell therapy included (median age in years [interquartile range], 60 [54 -70]; 40.0% female; 75.6% White, 7.3% Black, 8.4% Hispanic), 29 (6.2%) had ICANS. Having acute kidney injury (AKI) [aOR = 4.2, 95%CI: 1.6–10.1] or sepsis [aOR = 6.1, 95%CI: 1.9 - 19.4] were significantly associated with ICANS compared to those without these risk factors. Conclusions: In patients receiving CAR-T cell therapy, having AKI or sepsis was found to be associated with an increased risk of ICANS. These findings suggest that identifying patients who have AKI or sepsis preceding or during CAR-T cell therapy infusions may help predict which patients are at increased risk of ICANS.
Effect of cancer immunotherapy with CD39/PD-L1 bispecific antibody OriA631-b.
Authors: Xiaopei Li, Yuchen Zhang, Ze Yang, Qi Deng, Huajing Wang, Haiyan Zhu, Ligong Lu, Xian-Yang Li, Ryan Qu, Xiaowen He
Journal: Journal of Clinical Oncology (2024)

e14508 Background: Despite significant advancements in cancer immunotherapy through the use of immune checkpoint inhibitors, there remains a need for more robust strategies to enhance anti-tumor immune responses. This study introduces and characterizes OriA631-B, an innovative CD39/PD-L1 bispecific antibody. By simultaneously targeting the metabolic checkpoint CD39 and the immune checkpoint PD-L1, this novel antibody has the potential to significantly augment anti-tumor efficacy, particularly in cold tumors characterized by a scarcity of infiltrating immune cells. The development of OriA631-B marks a breakthrough in concurrently addressing two crucial immunosuppressive pathways. Methods: The creation of OriA631-B involved cutting-edge antibody engineering methodologies to guarantee optimal binding affinity and specificity for its target antigens, CD39 and PD-L1. With meticulous design and refinement, OriA631-B was developed to exhibit robust binding capabilities to both CD39 and PD-L1, enabling simultaneous and precise recognition. Leveraging advanced antibody engineering techniques was instrumental in crafting OriA631-B as a potent tool with heightened binding properties, broadening its potential applications across diverse therapeutic contexts. Results: In vitro investigations revealed the efficacy of OriA631-B, derived from the foundation of a clinically validated in-house generated PD-L1 antibody (YN035). This innovative antibody effectively thwarted CD39-mediated adenosine production, resulting in heightened effector T cell function and proliferation. In vivo efficacy assessments conducted on syngeneic hot tumor models MC38 and Hepa1-6 underscored the remarkable effectiveness of OriA631, the CD39 monoclonal antibody (mAb), in controlling tumor growth. Notably, OriA631-B, the CD39/PD-L1 bispecific antibody, exhibited even more profound impacts, significantly restraining tumor growth beyond the effects observed with single-target treatments in the hot tumor model or combination therapies in both the hot tumor model MC38 and the cold tumor model CT26. These findings underscore the potent therapeutic potential of OriA631-B and its capacity to exert robust anti-tumor activity by concurrently targeting CD39 and PD-L1. Additionally, safety profiling revealed an acceptable toxicity profile for OriA631-B, with no significant adverse events observed during the study. Conclusions: In summary, OriA631-B demonstrates potential as an innovative immunotherapeutic strategy for cancer treatment by concurrently targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion. Further exploration, including clinical trials, is imperative to fully uncover the therapeutic capabilities of this groundbreaking bispecific antibody in cancer immunotherapy.
Cardiotoxicity of immune checkpoint inhibitors: A retrospective cohort study of 93,362 patients.
Authors: Hasti Barzkar, Brittany Miles, Ankit Mehta
Journal: Journal of Clinical Oncology (2024)

e14529 Background: The advent of immune checkpoint inhibitors (ICI) as therapy for a wide array of cancer types has extended patient survival and propelled the field of oncology into a new era. However, notable immune-related adverse events have been observed that transgress self-tolerance. Among these adverse events, myocarditis is emerging as a serious and often lethal toxicity. This study aims to assess whether a significant association exists between immune checkpoint inhibitors and myocarditis and/or pericarditis. Methods: The TriNetX research network was used for this study. Two patient cohorts were created by using International Classification of Disease 10 (ICD-10) codes and HCPCS codes. Both patient cohorts consisted of patients with malignancy (C00-D49) and no history of myocarditis. One cohort was treated with immunotherapy while the other was excluded from such exposure (HCPCS codes were used for ipilimumab, nivolumab, pembrolizumab, and durvalumab). The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm, resulting in 46,681 patients in each arm. They were then evaluated for the development of myocarditis or pericarditis (I51.4, I31, I30) over the subsequent 5 years. Results: Cancer patients treated with immunotherapy were significantly more likely to experience myocarditis or pericarditis than those who did not receive those agents (7% vs 1.2%, RR 5.8, 95% CI (5.33,6.36), P value &lt;0.0001). Conclusions: This study suggests a significant association between the use of immunotherapy agents and the development of myocarditis and pericarditis. Further studies are necessary to better delineate the mechanism by which these cardiac toxicities occur, establish guidelines for surveillance of its onset, and discover how to suppress the immune-toxicities while retaining anti-tumor effect.
Impact of time-of-day infusion of camrelizumab combined with chemotherapy on efficacy in advanced malignant tumors.
Authors: Li-Yue Sun, Xian Xu, Quan-An Xu, Ke-Xin Xian, Xin-Xin Zeng, Hua-Gen Li, Xu-Hui Zhang
Journal: Journal of Clinical Oncology (2024)

e14634 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has emerged as a standard first-line treatment strategy for advanced cancers. Camrelizumab and Tislelizumab, representative ICIs, have approval by the Chinese NMPA for first-line treatment of advanced cancers such as lung cancer and esophageal cancer. Previous studies have indicated that the timing of drug administration can influence the efficacy of ICIs. However, studies on the ICIs plus chemotherapy are lacking. Therefore, we conducted a retrospective study to explore the effect of the timing of infusion on patients with advanced cancer undergoing treatment with ICIs combined chemotherapy. Methods: We retrospectively enrolled a total of 253 patients diagnosed with advanced cancers between 2017 and 2023 in Guangdong Second Provincial General Hospital. Among these patients, 109 received camrelizumab (Cam cohort) plus chemotherapy and 65 received tislelizumab (Tis cohort) plus chemotherapy. Patients were grouped into morning (AM) and afternoon (PM) categories based on the timing of their ICIs administration (&lt; 1 times versus ≥ 1 times after 16:00). The Response Evaluation Criteria in Solid Tumors Criteria V.1.1 was used to evaluate the response to treatment. The primary endpoint was progression-free survival (PFS). Results: The results consistently showed that the PM group had a longer PFS than the AM group in the overall patients (p &lt; 0.01). In the Cam cohort, the PM group (n = 48) exhibited a longer PFS compared to the AM group (n = 61) (16.8 months vs. -, p = 0.02). However, no significant difference in PFS was observed among patients in the Tis cohort (AM vs. PM, n = 34 vs. n = 31, 16.1 months vs. -, p = 0.51). Subgroup analyses indicated that the PM group had a more favorable PFS treatment effect in most subgroups. The incidence of any Treatment Emerged Adverse Event (TEAE) (Cam cohort, AM vs. PM, 98.52% vs. 92.68%; Tis cohort, AM vs. PM, 97.05% vs. 100.00%) and grade 3 TEAEs (Cam cohort, AM vs. PM, 5.80% vs.7.30%; Tis cohort, AM vs.PM - vs. 12.90%) was similar in the Cam cohort and Tis cohort. The most common adverse events are anemia (Cam cohort vs. Tis cohort, 70.58% vs. 79.41%), thrombocytopenia (Cam cohort vs. Tis cohort, 54.41% vs. 58.82%) and lymphopenia (Cam cohort vs. Tis cohort, 44.11% vs. 44.11%). Conclusions: The findings of this study highlight a significant variation in daily rhythms among advanced cancer patients undergoing treatment with ICIs plus chemotherapy. Interestingly, a trend was observed in patients treated with camrelizumab, where those receiving treatment in the afternoon demonstrated a longer PFS. However, this trend was not observed in patients treated with tislelizumab. These results suggest that time-of-day infusion could potentially serve as a personalized strategy for patients treated with combination ICIs therapy.
The pan-cancer landscape of SMARCA4 and SMARCB1 alterations in a large cohort of Chinese patients.
Authors: Qingling Song, Junjie Xie, Minxiao Guan, Huijia Wu, Yanling Lv, Mengdi Yuan, Yu Wang, Jiaxing Zhao, Zeyu Jiang, Yafei Zhang, Xingxiang Pu
Journal: Journal of Clinical Oncology (2024)

e14636 Background: Alterations of SMARCA4 or SMARCB1 (SMARCA4/B1) proteins have been identified in various aggressive cancers. Recent studies show that tumors harboring deleterious SMARCA4/B1 alterations express PD-L1 and respond to immune checkpoint inhibitor (ICI) therapies. Current ongoing immunotherapy-based clinical trials for cancers deficient in SMARCA4/B1 include combinations of atezolizumab and the TIGIT antibody tiragolumab (Phase II), as well as nivolumab and the CTLA-4 antibody ipilimumab (Phases II &amp; III). Here we present a comprehensive analysis of the pan-cancer landscape of SMARCA4/B1 alterations, based on real-world data from a large cohort of Chinese patients. Methods: From 2021 to 2023, we collected genomic information from 16,113 cancer patients, spanning more than 40 different cancer types. These patients had undergone targeted next-generation sequencing (NGS) through the Med1CDx panel, which targets 601 cancer-associated genes. After excluding 1,034 samples of unidentified tumor origins, 15,079 samples were analyzed further. The analysis included somatic and germline pathogenic/likely pathogenic (P/LP) single-nucleotide variants, insertions/deletions, and copy number alteration in SMARCA4/B1. Results: We identified 421/15079 (2.8%) patients with SMARCA4/B1 alterations, with a median age of 63 years (range 13-90). Cancer types with a higher frequency of SMARCA4/CB1 mutations include: endometrial cancer (9.8%), thyroid cancer (6.9%), gastric cancer (6.2%), cholangiocarcinoma (5.7%), and lung cancer (4.4%). The predominant mutation type is variants of uncertain significance (VUS) gene mutations, constituting 72% (302/421) of the spectrum, with nearly all being missense mutations. These are mainly observed in lung cancer, thyroid cancer, and colorectal cancer. The frequency of pathogenic/likely pathogenic mutations is 28% (119/421), mainly distributed in lung cancer and liver cancer. Q201L, P222L, and E1364del are the most common mutations in SMARCA4, with a mutation rate of approximately 4.1%, occurring across over five cancer types. The most common co-mutations of SMARCA4/B1 were TP53 (47.3%), EGFR (25.4%), KRAS (15.9%), STK11 (7.1%) and CDKN2A (7.4%). Clinicopathological feature of age showed no significant differences between SMARCA4/B1 mutant and wild-type groups. Tissues with SMARCA4/B1 mutations exhibited a higher tumor mutational burden (TMB) (median=8.3) than wild-type tissues (median=4.2) (P &lt; 0.001). Conclusions: Elevated TMB levels in patients with SMARCA4/B1 mutations suggest a significant potential benefit from immunotherapy. The presence of co-mutations may also aid in predicting the efficacy of combination immunotherapy treatments. Furthermore, the high prevalence of VUS emphasizes the need for additional research to determine their clinical relevance.
Potential of near real-time detection of cancer and immuno-oncology failure, within weeks of initiating therapy.
Authors: Floyd Taub, Matthew Russo, Suzin Mayerson Wright, Charles Henry
Journal: Journal of Clinical Oncology (2024)

e14555 Background: For most areas of internal medical practice, biochemical and/or clinical tests rapidly allow physicians to evaluate if a drug being administered has activity in that patient. Unfortunately, for most of oncology, measuring response is by imaging after delay of months. Methods: In 2018 the Trau lab published that the pan-cancer DNA methylation pattern (general hypomethylation with specific hypermethylation) resulted in physico-chemical alteration in purified circulating tumor DNA (ctDNA) as well as genomic DNA. Detecting these changes were not sequence dependent, but rather the epigenetic alterations resulted in altered binding to a specific electrode, easily and quickly measured by differential pulse voltammetry. In 2022 our group using the “aiElectrode” method showed significantly improved ability to cleanly separate cfDNA from people with cancer and those without, as well as anecdotal success in using the method to separate progression from regression. The improved method is used here. Results: Here we present analysis of samples from 18 cancer patients from 3 small series with cfDNA taken before and after treatment; 20 pairs could be analyzed. The Scripps Clinic Bio-Repository supplied samples from 8 lymphoma patients before and after treatment with chemotherapy and a bone marrow transplant; all showed initially clinical improvement and decrease in the ctDNA by the aiElectrode. Subsequently 2 relapsed and in both cases ctDNA analysis showed increased ctDNA. The Drammen Hospital in Norway supplied 18 samples from 7 patients (2 or 3 time points each) with NSCLC treated with pembrolizumab immunotherapy. One responded and 6 had progression. The aiElectrode ctDNA results were concordant for all but one of the 7 patients. The University of Colorado provided before and after therapy specimens from three patients. In total, 20 pairs of specimens were analyzed and 19 were concordant, generating an accuracy of 95%. Some of the post treatment samples from Drammen were as early as 2 weeks after therapy initiation. Conclusions: As IO may result in cures, but also may result in pseudoprogression or hyperprogression, a simple, rapid turnaround, inexpensive, blood test to aid clinicians in the early detection of failing IO, and thus individualized switching to an alternative therapy (which typically costs much less) may be beneficial, even life saving for that patient, while reducing direct as well as indirect costs. Unlike other ctDNA technologies, this can eventually be offered in a small, point-of-care device that is simple and inexpensive enough for use at every oncologist office visit to provide near real-time tracking of treatment response. [Table: see text]