bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between bispecific T cell engager (BiTE) therapy and inflammatory adverse effects (AEs) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Xu Michael , Wummer Brandon , Kelly William Kevin , Bashir Babar
Published: June 2023

e14534

Background: Cancer immunotherapies have offered limited efficacy in treating mCRPC. A novel class of immunotherapy are BiTEs, which target both a specific cancer antigen and CD3 to enhance T cell anti-tumor activity. Although BiTEs are a promising avenue for cancer research, their safety profiles are not well-understood. Thus far, it is known that first-in-class blinatumomab is associated with AEs such as cytokine release syndrome, neurotoxicity, and febrile neutropenia. Given their mechanism of action and possible propensity to produce a general inflammatory environment, we aimed to explore the systemic and inflammatory AEs of BiTEs in mCRPC patients. Methods: A retrospective chart review was performed on an IRB-approved database. Inclusion criteria included a history of mCRPC and BiTE therapy. There were no exclusion criteria. Study objectives were to evaluate whether BiTE therapy led to de novo inflammatory AEs or exacerbation of pre-existing inflammatory disorders. AEs were defined/graded as immune system disorders per Common Terminology Criteria for Adverse Effects v5.0. Results: 24 mCRPC patients in our clinic received at least 1 dose of BiTE therapy. Mean (range) age was 67.3 (54-79) years. 5 (20.8%) had pre-existing inflammatory disorders. Mean (range) treatment course was 14 (0-44) weeks. 6 (25.0%) discontinued due to inflammatory AEs, 15 (62.5%) discontinued due to disease progression, 1 (4.2%) discontinued due to noncompliance, and 2 (8.4%) are currently on BiTE therapy. Notable de novo AEs included arthralgia (8.4%), thrombophlebitis (8.4%), myocarditis (4.2%), giant cell arteritis (4.2%), and pneumonitis (4.2%). Patients with pre-existing inflammatory conditions (5/5) were statistically more likely to develop inflammatory AEs after BiTE therapy initiation compared to those without (4/19) (p < 0.01). Of the 9 patients who developed inflammatory AEs, 6 (66.7%) developed inflammatory AEs after the first dose of BiTE therapy. After the first dose, mean C-reactive protein was significantly elevated in patients with pre-existing inflammatory conditions (10.0) compared to those without (1.6) (p = 0.041). Conclusions: Our analysis suggests that BiTE therapies are associated with inflammatory AEs other than cytokine release syndrome, neurotoxicity, and febrile neutropenia. In particular, some of our patients developed vasculitis, myocarditis, or pneumonitis. Furthermore, patients with pre-existing inflammatory conditions are at significantly greater risk of developing inflammatory AEs compared to patients without pre-existing inflammatory conditions. Thus, patients with pre-existing inflammatory conditions who are receiving BiTE therapy should be cautiously observed. Additional data from larger BiTE therapy clinical trials is needed to further support these findings.
The practice of thyroid monitoring in patients treated with lenalidomide for hematological malignancies: A single-center retrospective analysis.
Authors: lakra rachaita , Hassan Zara , Ramadas Poornima
Published: June 2023

e14535

Background: Thyroid dysfunction in the form of both hypothyroidism and hyperthyroidism is a known fact and is seen in 5-10 % of patients treated with Lenalidomide. Since the potential impact of thyroid disease on a patient being treated for malignancies can be devastating, surveillance evaluation of thyroid function has been recommended on a bi-monthly basis. This single center retrospective analysis is an effort to understand if this recommendation is practiced by hematologists. Methods: Data for this retrospective chart review was extracted from electronic medical records. 225 patients who received Lenalidomide from the year January 2019 to October 2022 were included. Thyroid monitoring was estimated through thyroid stimulating hormone (TSH) if done and was further classified as baseline (TSH before lenalidomide initiation) versus three months. Abnormal thyroid testing was perceived as TSH outside of our institute’s normal range (0.40-4.0 uIU/mL). Any other risk factors of developing thyroid disease (neck radiation exposure, autoimmune disorders or other drugs contributing to thyroid disfunction) were also recorded. Descriptive statistics with interquartile ranges and frequencies were analyzed. Results: Doses of Lenalidomide used ranged between 5 and 25 mg, over a time period ranging between 1 and 48 months. Reasons for discontinuation of Lenalidomide included bone marrow suppression (N=32, 14%), neuropathy (N=14, 0.06%), intolerable fatigue (N=7, 0.03%) and one patient had concerns for drug induced hypothyroidism. Seven patients were found to have pre-existing thyroid disease, which was well controlled with replacement before initiation of Lenalidomide. 52% had a baseline TSH documented prior to initiation of treatment, while only 18 patients (0.08%), had three monthly thyroid monitoring. Conclusions: Lenalidomide caused hypothyroidism was seen in one of our patients, however 48% never had a TSH documented, while 99.2% were not monitored as per recommendations. This study reflects on the principle of “primum non nocere” and adequate treatment of missed thyroid anomalies in patients treated with lenalidomide can improve quality of life. We recommend hard reminders of bi-monthly TSH monitoring through electronic medical record, for patients receiving Lenalidomide which has been initiated in our institute post this study.
Pressurized intra-peritoneal aerosol as a delivery system for macrophage reprogramming cellular therapy in conjunction with chemotherapy for the treatment of advanced peritoneal malignancies.
Authors: Ben-Yaacov Almog , Adileh Mohammad , Hershkovitz Oren , Galamidi Einat , Amor Veronique , Binder Lior , Mevorach Dror , Nissan Aviram
Published: June 2023

e14537

Background: Novel intraperitoneal delivery systems like Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC) increase the therapeutic access with encouraging responses in patients with peritoneal carcinomatosis unresponsive to systemic therapy. However, survival rates remain at 11-16 months, and treatment options are limited, especially in patients with high tumor burden. Allocetra, an innovative immunomodulatory cellular therapy, has demonstrated antitumor activity in preclinical peritoneal tumor models, reprogramming macrophage function in the tumor microenvironment. The clinical study assesses the applicability and safety of Allocetra given by pressurized intra-peritoneal aerosol, in conjunction with PIPAC. Methods: Allocetra is manufactured from mononuclear cells collected from healthy non-matched donors, and induced to undergo early apoptosis. Safety of administration via pressurized aerosol was assessed by cell recovery and function. The clinical study is a dose-finding safety study with inter- and intra-patient dose escalation of Allocetra to determine safety of intraperitoneal Allocetra administration via pressurized aerosol system (Capnopen, Capnomed, Germany), with PIPAC. Patients have advanced peritoneal cancer, non-eligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Two cohorts (n=3) are treated with escalating doses of Allocetra at 6-week intervals. Two subsequent cohorts (n=3) include patients treated at the maximal tolerated dose, to evaluate the sequencing of Allocetra and PIPAC. Results: Allocetra pressurized aerosol delivery demonstrated stable and acceptable cellular profiles, recovery and potency. In the first clinical cohort (n=3), patients received escalating doses of 1 x 109, 2.5 x 109 and 5 x 109 Allocetra cells, followed by PIPAC. Patients’ primary diseases were advanced colon and appendicular carcinomas with multiple prior treatment cycles (chemotherapy, biologics and immunotherapy). Patients were followed for a median 15 weeks (range 7-32) for adverse events. Adverse event profile following combined treatment with Allocetra included mostly mild common post surgical events: abdominal pain, pain around surgical wound, shoulder pain, abdominal wall hematoma, rash around surgical wound, urinary tract infection, inferior epigastric artery bleeding, and infected hematoma. None were considered related to Allocetra. All the patients are alive and continue to be followed. Conclusions: Initial results from the study indicate a favorable safety profile following pressurized intra-peritoneal aerosol administration of Allocetra cellular therapy. Additional patients will be treated with escalating doses of Allocetra to assess safety and initial response to treatment. Clinical trial information: NCT05431907 .
Safety and efficacy of loading-dose thymosin α1 in patients with advanced and refractory solid tumors with lower absolute T lymphocyte.
Authors: Xu Meiling , Zhao Xiangrong , Kong Yuehong , Xing Pengfei , Zhang Junjun , Zhang Liyuan
Published: June 2023

e14543

Background: Nowadays immune checkpoint inhibitors (ICIs) has been reshaping the paradigm of cancer therapy, including various refractory advanced solid tumors. Many studies have shown that low baseline peripheral blood-based immune cells, such as lymphocytes, was one of the most relevant parameters associated with immunotherapy efficacy and prognosis. Thymosin a1, a synthetic polypeptide, has been demonstrated to increase the number of peripheral lymphocytes, especially T cells in patients with solid malignancies. In this current study, we aimed to evaluate the efficacy of loading-dose thymosin a1 (Ta-1) on peripheral lymphocytes and subpopulations in advanced solid tumors and identify how it affects the clinical outcome. Methods: Participants with confirmed the number of peripheral blood-based CD3+ T cells less than 0.5 ´ 109/L, advanced solid tumors that had progressed after standard treatment, or intolerance were enrolled. In this study, those received 3.2mg thymosin α1 subcutaneously in a daily loading dose for 7 days, and the peripheral blood immune indexes were detected on the ninth day. Afterwards, these patients were decided whether to receive radiotherapy and PD-(L)1 inhibitor based on the clinician’s judgement. The primary endpoint was overall survival (OS) and the secondary endpoint were treatment-related adverse events and a panel of circulating lymphocytic subpopulations. Results: As of the cutoff date of February 6th, 2023, a total of 27 patients were enrolled.The median age of them was 61 years old (range: 39-78). Twenty-two patients (81.5%) had poor ECOG performance status of 2 and 3. Eight (29.6%) patients had received at least 3 prior lines of systematic treatments. Most patients (19, 70.3%) had 2 or more metastatic sites. After treated daily with 3.2mg Ta-1 for 7 days, twenty-four patients (88.9%) were subsequently received radiotherapy and PD-(L)1 inhibitors. By data cut-off, median duration of follow-up was 19.2 months (95%CI: 6.2 to NA;), and median OS was 19.6 months (95%CI: 6.6 to 27.2). We found that peripheral CD3+T cells, CD3+CD4+ T cells, CD3+CD8+ T cells, and natural killer (NK) cells were significantly increased after Ta-1 treatment. In an attempt to identify whether the increasing number of lymphocytes after Ta-1 treatment affects the clinical outcome, we compared the subgroup with increasing rate≥30 with that < 30%, which showed a trend of longer median OS in ≥30 subgroup than < 30% (19.6 months vs 3.9 months). No Grade ≥3 treatment-related adverse events occurred in all enrolled patients when treated with loading-dose Ta-1. Conclusions: In this study, we demonstrated that a daily loading-dose Tα-1 treatment increased the number of peripheral lymphocytic subpopulations, and this effect appears to benefit survival outcomes, shedding new light for patients with advanced or refractory solid tumors when initiated ICI treatment.
Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer undergoing neoadjuvant chemotherapy: A comparison between patients with triple negative breast cancer (TNBC) and non-TNBC.
Authors: Smit Teresa , Rapoport Bernardo Leon , Steel Helen C. , Benn Carol , Nayler Simon , Heyman Liezl , Theron Annette J. , Hlatswayo Nomsa , Kwofie Luyanda LI , Meyer Pieter , Anderson Ronald
Published: June 2023

e14546

Background: Checkpoint proteins regulate the immune system. Breast cancer is associated with up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (sICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) and compare the biological behaviour of these sICMs between TNBC and non-TNBC patients. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data were prospectively obtained and levels were compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in the activation of CD8+ cytotoxic T cells, were significantly increased (p < 0.04-p < 0.00001). Four of the soluble co-inhibitory checkpoints (LAG-3, PDL1, TIM-3 and HVEM) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p < 0.03 and p < 0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints seemingly indicates a reversal of systemic immune dysregulation following the administration of NAC in early BC. In contrast, recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. No significant differences were detected between the changes of 16 sICMs levels at pre-NAC, post-NAC and post-surgery when comparing the TNBC and non-TNBC patients. Conclusions: This study demonstrates low levels of co-stimulatory and co-inhibitory sICMs in newly-diagnosed, non-metastatic BC pts. Following treatment with NAC, the sICMs levels increase substantially, except CTLA-4. In the case of co-stimulatory sICMs, these novel findings are indicative of an immune-restorative mechanism. The pattern of co-inhibitory sICMs (elevated levels of PD-L1, LAG-3, TIM-3 and HVEM), might be indicative of immune-therapeutic resistance, underscoring the augmentative immune-therapeutic promise of targeting these molecules, either individually or in combination, to improve the outcome of pts with early BC. These differences were not significant between TNBC and non-TNBC patients.
Outcomes of peritoneal metastases in mismatch repair deficient (dMMR) cancers treated with immune checkpoint inhibitors and variables associated with response.
Authors: Mosalem Osama M , Elhariri Ahmed , Wiest Nathaniel , Imperial Robin John Lester , Sonbol Mohamad B. , Jin Zhaohui , Jones Jeremy Clifton , Starr Jason S.
Published: June 2023

e14576

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many solid malignancies. ICI appears particularly effective when tumors exhibit high microsatellite instability (MSI-H) and/or mismatch repair deficient (dMMR) status. Although the response is typically quite good in this setting, there are scenarios where benefit is less than anticipated. In this study, we aimed to explore the efficacy of ICIs in patients with MSI-H/dMMR cancers with peritoneal metastasis (PM). Methods: We conducted a retrospective chart review to identify patients (pts) with PM from primary MSI-H/dMMR cancers treated with immunotherapy between 2010 and 2022 at Mayo Clinic. Data was collected to include pt demographics, tumor characteristics, pathology, tumor markers, imaging, mutational profile, and previous and subsequent treatments. The primary endpoint was disease control rate (DCR), defined as objective response rate (RECIST v1.1 criteria) or stable disease. Results: Forty-six pts with MSI-H/dMMR and PM treated with ICIs. Most of our cohort were female (61%) with a median age at diagnosis of 61 years. Colorectal cancer was the most common primary site (69.6%), followed by endometrial (6.5%). Most pts received treatment with PD-1 antibodies as second-line therapy following systemic chemotherapy. DCR of the PM was 71.6 % (n= 13 PR, 9 CR, and 9 SD), with a median duration of response of 12.6 months. Thirteen pts (28.4%) had progressive peritoneal disease on ICI with a median PFS of 2.2 months. Ascites was a poor prognosticator and predicted a lack of benefit from ICI (HR 6.6, 95% CI=2.24-19.9, p= 0.006). Mucinous and signet ring histology were common in pts with peritoneal progression (61.5%); however, this was not statistically significant (HR=1.6; 95%CI= 0.4383 to 3.899, p 0.5). Multivariate analysis for the presence or absence of BRAF and/or RAS mutations was not statistically significant in predicting response. Neither was the specific MMR gene mutation(i.e., MLH1 or PMS2). Interestingly, discordant responses between the peritoneum and other sites of metastasis to immunotherapy were seen in 13 pts (28.4%), primarily as primary peritoneal progression compared to other tumor sites. Conclusions: In our cohort, the DCR of metastatic peritoneal disease in MSI-H/dMMR tumors was approximately 71%. The presence of ascites was identified as a poor prognosticator in this setting and was associated with a lack of response/benefit from ICIs. Histologic subtype (i.e., mucinous/signet ring) did not show statistical significance in predicting ICI response. The subpopulation with discordant response to ICI suggests that peritoneal immunobiology may differ from other sites. Further research on immunotherapy response in the peritoneum is needed for this special subset of pts.
A study to evaluate the safety, tolerability, and efficacy of IBI939 in combination with sintilimab in patients with previously untreated locally advanced unresectable or metastatic PD-L1–selected non–small-cell lung cancer (NSCLC): Updated efficacy and safety results.
Authors: Wu Chunjiao , Liu Baogang , Wu Lin , Zhang Tongmei , Wang Ke , Miao Liyun , Wu Jingxun , Wang Huijuan , Fang Jian , Li Xingya , Zhang Wei , Hu Yanping , Mei Xiaodong , Song Yong , Zhu Jing , Xin Ying , He Yue , Chen Yuling , Ye Jiawei , Cheng Ying
Published: June 2023

e14578

Background: According to studies in patients (pts) with solid tumors, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) plays an important role in tumor immunosurveillance. The preliminary results showed that IBI939 plus sintilimab demonstrated improved PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC pts with no prior systemic treatment (Ying Cheng et al. ESMO-IO, 2022). Here we report updated efficacy and safety data of this study. Methods: Eligible pts with systemic treatment-naïve, advanced or metastatic NSCLC, PD-L1 TPS ≥ 50%, and driver gene negative were enrolled and randomized 2:1 to IBI939 20 mg/kg plus sintilimab 200 mg IV Q3W (arm A) or sintilimab 200 mg monotherapy IV Q3W (arm B). The primary objective was to evaluate the ORR per RECIST v1.1. The secondary objectives include evaluation of PFS per RECIST v1.1, OS, and safety. Results: Of 42 pts enrolled, 28 pts (median age: 65; adenocarcinoma: n=19; brain metastasis: n=7) and 14 pts (median age: 58; adenocarcinoma: n=6; brain metastasis: n=1) were in arm A and arm B, respectively. As of Jan 1st, 2023, with a median PFS follow-up of 12.2 months (95% CI, 11.1-13.9) in arm A and 11.3 months (95% CI, 10.8-13.6) in arm B. The median PFS per investigator was 13.2 months (95% CI, 6.7-16.5) in arm A vs 6.4 months (95% CI, 1.4-NA) in arm B (HR: 0.62; 95% CI, 0.26-1.43). All 42 pts were included for safety analysis. The overall safety profile was consistent with the latest previous report, with no new safety signals identified in each arm. The incidence of TRAEs was 96.4% vs 78.6% (5 pts in arm A and 6 pts in arm B experienced ≥ grade 3 events), respectively. Grade ≥ 3 immune-related AEs (determined by the investigator) were reported in 3 (10.7%) pts in arm A and 4 (28.6%) pts in arm B. All reported irAEs were manageable. One pt in each arm experienced TEAE leading to end of treatment. There was no TEAE leading to death happened in arm A. Two pts experienced grade 5 TEAE in arm B, which was unknown cause of death and respiratory failure. Conclusions: With longer follow-up time, IBI939 plus sintilimab demonstrated durable PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC patients with no prior systemic treatment. Clinical trial information: NCT04672369 .
Effect of machine learning-based integration develops M2 macrophage-activation genes signature on outcomes in nasopharyngeal carcinoma.
Authors: Huang Zongwei , Li Ying , Chen Xiaochuan , Qiu Sufang
Published: June 2023

e14581

Background: The M2 macrophages are independent prognostic factors in nasopharyngeal carcinoma (NPC). Nevertheless, the clinical significance of M2 macrophages remains largely unexplored. Methods: We applied public single-cell sequencing data (GSE150825) to reconstruct a pseudotime trajectory of macrophage polarization in NPC and analyzed the gene expression patterns along the trajectory. GeneSwitches was used to identify the order of the critical regulatory gene during M2 macrophage activation. A novel computational framework was constructed to screen the M2 macrophage-activation genes (MAGens) for developing MAGens signature by integratively analyzing the transcriptomes data of single-cell, published dataset (GSE102349, N=88) and Fujian NPC dataset (N=188) using 10 machine learning algorithms (101 combinations). Results: Combining single-cell transcriptomics with GeneSwitches analyse, we identified SPP1 as the top switching gene and the order at which the switch takes place for the state of M2 macrophage activation. At the bulk transcriptome level, we found that the high expression of SPP1 had poor prognosis and more infiltration of M2 macrophages. Immunohistochemistry was used to validate the association between the critical regulatory gene expression and M2 macrophages. Then we analyzed the differential expressed genes (DEGs) upregulated by M2 macrophages at the single-cell transcript level. And the NPC transcriptome data was used to identify SPP1-related genes and prognostic genes. Based on the share genes of M2 macrophage DEGs，SPP1-related genes and prognostic genes, we established a five-gene MAGens signature which exhibited highly diagnostic accuracy in predicting progression-free survival in patients with NPC. Conclusions: We explored the role of SPP1 in NPC progression, M2 macrophage polarization and established an MAGens signature related prognostic model for NPC. MAGens signature could serve as a robust and promising tool to improve clinical outcomes for individual NPC patients.
Pharmacokinetics (PK) of epacadostat in combination with sirolimus in advanced malignancy.
Authors: Huang Chao Hui , Komiya Takefumi , Kasi Anup , Williamson Stephen K. , Weir Scott James , Baranda Joaquina Celebre
Published: June 2023

e14589

Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients (pts) with advanced solid tumors and performed PK studies. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at d -7 followed by 1mg/d with E added on d1 of Cycle(C) 1 starting at 100mg bid in a 28d C at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400mg bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. PK samples from plasma samples for determination of plasma E concentrations were obtained on C1d1, prior to administration of the first E dose. Plasma samples were also obtained on C1d1 at two hours post-dose, coinciding with the previously reported Tmax for E. For pts continuing E treatment, plasma samples were obtained on C2d1, prior to dosing (representing trough drug concentrations) as well as at two hours (representing Cssmax). Results: The phase I study enrolled 15 pts. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). Mean values as well as the range of plasma E concentrations observed in the three dose cohorts at each collection time are summarized. Conclusions: The combination of SE showed results consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion. Plasma concentrations of E observed across the three dose cohorts are also consistent with those previously reported. Due the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality. Mean (range) plasma E concentrations (ng/mL) determined in samples obtained from pts at trough and two hours post-dose during treatment C1 and C2. Clinical trial information: NCT03217669 . [Table: see text]
T cell redirecting and TLR7/8 agonist encapsulated liposomes targeting HER2+ tumors: Preclinical efficacy, pharmacokinetics and safety evaluations.
Authors: Zheng Anjie , Jin Shanshan , Wang Shuhang , Wu Xuan , Xie Danting , Long Jinfeng , Dai Yongchao , Xu Fengwei , Li Ning , Xu Yuhong
Published: June 2023

e14590

Background: T-cell dependent bispecific antibodies (TDBs) have shown limited success in solid tumor treatments. We hypothesized that it may be due to TDBs limited distribution in solid tumor tissues. We therefore propose to take advantage of the EPR (enhanced permeability and retention) effect of the liposome system to improve the PKPD properties of TDBs. The liposomes are named TRAFsomes (T cell Redirecting Antibody Fragment-anchored Liposomes). HF5050 is a TRAFsome containing on average 6 anti-CD3 and 10 anti-Her2 on each liposome surface and the toll-like TLR-7/8 agonist Resiquimod encapsulated inside at specific lipid to drug ratios. It preclinical efficacy, pharmacokinetics and safety evaluation studies are conducted to support the IND application. Methods: The T cell redirecting and target specific cytotoxic effect of HF5050 were evaluated in five PBMC co-cultured cancer cell models with different Her2 expression. Tumor cells derived from adenoid cystic carcinoma tumor tissues was also included. T cell redirection and activation are examined by T cell surface markers CD25/CD69 and secretion of IFN gamma, Perforin, and granzymes B in the absence and presence of cancer cells. For the incorporation of TLR7/8 agonist Resiquimod, we evaluated the effect of drug dose by varying the drug loading ratios in order to achieve a synergistic effect. For the in vivo efficacy studies, the N87 gastric cancer CDX model and an adenoid cystic carcinoma tumor PDX model were set on PBMC reconstructed humanized NCG-B2M mice. Pharmacokinetic and tissue distribution studies are carried out in tumor bearing mouse models as well. Results: HF5050 has shown to be a highly effective anti-cancer agent in both in vitro and in vivo studies. It mediates T cells-tumor cells redirection and cytotoxicity in a dose-dependent manner, especially in Her-2 highly expressing cell lines. HF5050 also effectively stimulates T cell activation and displays high efficacy in PBMC reconstruct humanized NCG-B2M tumor-bearing mice. Pharmacokinetic research confirms liposome successfully maintains drug levels in the bloodstream, and improves drug accumulation within tumor tissues. Conclusions: Overall, these data demonstrate that HF5050 processing a novel cell bridging function between T cells and tumor cells, and with the capability of activating immune cells. Based on the encouraging preclinical results, HF5050 exhibits promising development potential.
A phase I/II trial of NOX66 in combination with nivolumab in patients (pts) with advanced cancer.
Authors: de Souza Paul L. , Gao Bo , Marx Gavin M. , Cooper Adam James , Wilkinson Kate Jessica , McPherson Luke , Erskine Amy , Nixdorf Sheri , Putterill Leigh , Mann Timothy , Sajinovic Mila , Fatima Shadma , Scott Kieran
Published: June 2023

e14591

Background: NOX66 (idronoxil) targets ENOX2 and suppresses STING-mediated inflammatory pathways, reducing IFN and NFκB driven cytokine production by cancer cells. Adding NOX66 to nivolumab may help overcome resistance mechanisms to checkpoint inhibitors and improve responses in patients. Methods: IONIC-1, is an open label Phase I/II trial evaluating safety and preliminary efficacy of NOX66 (suppositories daily x 1 week, then 1 week rest) combined with nivolumab (240mg IV every 2 weeks). Three dose cohorts of NOX66 are planned (1200mg daily, 1800mg daily, 2400mg daily). Objectives include safety, tolerability, and clinical and radiological responses. Two groups are being studied: 1) Pts who have prior progression on a checkpoint inhibitor; 2) Pts naïve to checkpoint inhibitors. Results: 11 pts have been treated to date; 3 in Group 1, and 8 in Group 2. All pts have received at least 2 cycles of the combination treatment; 2 pts completed 8 cycles, and 2 pts remain on study. Tumour types include lung, prostate, gastric, pancreatic, nasopharyngeal and metastatic squamous carcinoma. Early signals of tumour response based on RECIST 1.1 criteria include stable disease in 2 pts (SD at 8 weeks and at 16 weeks); partial response (PR) in 1 patient at 16 weeks; complete response (CR) in 2 pts, both with ongoing CR at 24 weeks. Five pts had disease progression, and 1 pt was withdrawn due to suspected immune mediated myositis and hepatitis resulting from nivolumab and was not evaluable. The most common AE was local perineal irritation, readily managed with topical corticosteroid cream. Two pts developed an erythematous rash over the trunk and limbs after 2 cycles, suspected to be related to the combination treatment. Using a 32 multiplexed immune cytokine assay to evaluate the single-cell functional states of CD4+ and CD8+ T cells in patients’ peripheral blood mononuclear cells (PBMCs) at pre-treatment and at Cycle 3 Day 1, we found a significant increase in polyfunctionality in both effector CD4+ and CD8+ve T cells compared to baseline in responder patients. Conclusions: Preliminary analysis shows promising tumour responses from the combination therapy which appears to be well-tolerated, with no safety signals evident to date. Clinical trial information: ACTRN12621001537842 .
A functional immuno-oncology (IO) assay to assess patient response to immunotherapeutics in metastatic disease.
Authors: Hsu Shiaowen David , Hammer Joshua , Wang Lihua , Steele Shaun , Rupprecht Gabrielle , Wang Zhaohui , Metzger Steven
Published: June 2023

e14592

Background: Immuno-Oncology (IO) therapy such as anti-PD1 and anti-CTLA4 blockade has rapidly become the standard of care in melanoma, lung, and other solid tumors. However, current biomarkers such as PDL1 expression (TPS/CPS) do not accurately predict which patients will respond to anti-PD1 therapy. There is an unmet clinical need to develop better assays to predict which cancer patients will derive benefit from anti-PD1 and anti-CTLA4 therapy. Our recently developed MicroOrganoSpheres (MOSTM) technology partitions patient tumor samples into many tiny droplets containing the patient's native tumor microenvironment, including immune cells. The patients’ MOS can then be divided across multiple test conditions, enabling the development of a functional IO assay to predict response to IO therapy. Methods: Patient tumor samples from lung, melanoma, hepatocellular carcinoma (HCC), and colorectal cancer (CRC) containing resident immune cells were partitioned into individual immunologically active MOS. Tissue digest and culture conditions were optimized to maintain native immune cell viability and functionality for 8 days, enabling immune-mediated response to immune checkpoint inhibitors to be assessed using a variety of bioanalytic methods. MOS were dosed with nivolumab/panitumumab (anti-PD1 inhibitor), atezolizumab (anti-PDL1 inhibitor), ipilimumab (anti CLTA-4 inhibitor) or an isotype control antibody (IgG). Biological response was assessed using a combination of flow cytometry, imaging, and ELISA based high-sensitivity interferon gamma (IFNy) secretion quantification. Results: Using 35 cancer specimens including lung, melanoma, ovarian and renal cell carcinoma (RCC), a functional IO assay was developed to assess cell populations within patient-derived MOS, including relevant T cell populations, and characterize IFNy secretion after exposure to immunotherapy. The assay was then validated on three patient samples with metastatic HCC, melanoma, and MSI CRC. The samples were first interrogated using the optimized immunotherapeutic assay to determine cell populations within MOS by flow cytometry, imaging including immunofluorescence labeling of cell populations, and functionality by IFNy secretion quantification, to generate aMOS IO Index (MII) with MII < 1 representing no response to therapy and MII > 1 representing response to therapy. Of the three samples, the HCC had a MII < 1 while the melanoma and CRCr had MII > 1. Each patient subsequently received either anti-PD1/PDL1 and/or anti-CTLA therapy and their response to therapy was predicted by their MII. Conclusions: These preliminary data suggest our immunotherapeutic assay represents a first-of-its-kind functional assessment that can potentially predict patient response to immune checkpoint inhibitors. Further validations of our assay are now underway in our functional precision oncology MOS IO trial.
The first cold atmospheric plasma phase I clinical trial for the treatment of advanced solid tumors: A novel 4th treatment arm for cancer.
Authors: Canady Jerome , Cheng Xiaoqian , Zhuang Taisen , Murthy Saravana , Nissan Aviram , Gitelis Steven , Ly Lawan , Jones Olivia , Adele Mohammad , Blank Alan T. , O'Donoghue Cristina , Stenson Kerstin , O'Hara Karen , Keidar Michael , Basadonna Giacomo
Published: June 2023

e14596

Background: Local recurrence contributes to the poor prognosis for patients with Stage IV metastatic or recurrent solid tumors, despite advances in standard care. We report the clinical outcome of intra-operative Cold Atmospheric Plasma (CAP) combined with standard surgical procedures. Methods: The trial was a Phase I, multi-center, open-label, prospective, controlled study. Eligible patients undergoing surgery for advanced Stage IV metastatic or recurrent solid tumors were enrolled and preoperative treatments (neoadjuvant chemotherapy, immunotherapy, radiation, and primary surgery) were permitted. Participants were recruited from Rush University Medical Center in Chicago, Illinois and Sheba Medical Center in Tel HaShomer, Israel. Twenty patients (age 26-85 years) between March 2020 to April 2021 received intra-operative CAP treatment following surgical macroscopic tumor removal. The primary endpoint was safety, and the secondary endpoint was ablation of the local microscopic tumor bed without damaging the surrounding normal tissue. Results: Physiological data (blood pressure, pulse, body temperature, End Tidal CO2, and oxygen saturation) was recorded continuously throughout surgery. There were no significant changes (p > 0.05) during intra-operative CAP treatment. One adverse event grade 3 or higher was reported but no adverse events were related to CAP. As of February 13, 2023, 10 patients died of their disease between 3-32 months. Kaplan-Meier overall survival curves show the interim 31-month rate is 24% (95% confidence interval [CI], 5.0 – 100.0%). Median survival is 23 months. For R0 patients, the Kaplan Meier local non-recurrence probability showed that the interim 28-month rate is 75% (n=8; 95% CI, 50.3 – 100.0%) as of February 13, 2023. Histological staining, TUNEL assay, and confocal imaging of the surgical margins revealed cancer cell death and no damage to the surrounding normal tissue. Primary culture of the tumor confirmed total cessation of cancer cell survival. Conclusions: CAP treatment in combination with surgery for high-risk stage IV solid tumors is safe and induces cancer cell death at the surgical bed without damaging non-cancerous tissue. The survival rate in R0-resected CAP-treated patients was significantly improved compared to R1 and R2 patients and local non-recurrence rate for R0 patients was noteworthy. Clinical trial information: NCT04267575 . [Table: see text]
COVID-19 induced remission of biliary and renal cell carcinomas.
Authors: Tan Jocelyn L
Published: June 2023

e14598

Background: Clear cell renal carcinoma and cholangiocarcinoma are resistant to standard therapy. Complete remissions are rare. SARS-CoV-2 (COVID-19) boosts anti-viral immune responses but effects on cancers are unknown. Case reports of hematologic cancer remissions after COVID infection are emerging. Anti PD1/PD-L1 antibody therapy have prolonged remission in 20% of solid tumor patients. mRNA COVID-19 vaccines and COVID-19 active infections create anti-viral immune responses - increased IgG titers, SARS-CoV-2-specific antibodies, and boost T-cell response. Anti PD-1/PD-L1 antibodies immune responses, are presumed independent of the immune response to COVID vaccination/infection. Two previous case reports of hematologic remission were seen after COVID infection. (Hodgkins, multiple myeloma). There are no cases of solid cancer remission after COVID-19 exposure. Methods: Three patients with solid cancers and complete/near complete radiographic remissions after COVID-19 exposure. Two on low carbohydrate diets. History, dietary course and clinical outcomes are presented. Results: Case 1: 58 year old male diagnosed with stage IV clear cell renal carcinoma (lung nodules, mediastinal nodes). After 5 years he progressed on Sunitinib and began Nivolumab. His cancer stabilized but hypophysitis, diarrhea, severe jaw pain ended his treatment. After COVID-19 booster vaccine, he became anorexic, lost 50 lbs over 8 weeks (267 to 211 lb). Relapse was suspected but PET CT showed complete resolution of his lung nodules and adenopathy. Asymptomatic and in remission over 9 months post vaccine. Case 2: 51 year old male heavily pretreated stage 4 renal cell cancer, bone, liver, nodal metastases. On Nivolumab with stable disease but after COVID booster vaccine had high fever, fatigue, myalgia. PET CT scans later showed near complete resolution of his bony, hepatic and nodal metastatic sites. Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab. COVID-19 infection was followed by complete radiographic remission. Conclusions: Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy. Both followed low glycemic diets. Third case was a complete remission of biliary cancer after an acute COVID-19 infection. Proposed anti-cancer mechanisms - pathogen specific T cell action, anti-inflammatory effects against COVID-19 infection, cross-reactivity against tumor antigens, natural killer cell activation. COVID-19 proteins have oncolytic properties - HIV related B cell apoptosis and Coxsackievirus A21 oncolytic effects on myeloma and CD138+ plasma cells via intercellular adhesion molecule interaction. COVID-19’s effects plus the anti PD-1/PD-L1 antibodies immune response may be synergistic and merits further research.
Are severe immune-related adverse events more likely in patients with pre-existing autoimmune disease?
Authors: Isaacs Dayna Jill , Hilder Robin , Drakaki Alexandra , Lechner Melissa G
Published: June 2023

e14599

Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.
The association between body mass index and immune checkpoint inhibitors outcomes in melanoma: Results from real-world data.
Authors: Elantably Dina , Wang Jiasheng , Al Armashi Abdul Rahman , Al Zubaidi Anas , Alkrekshi Akram
Published: June 2023

e14604

Background: The “obesity paradox” refers to increase cancer risk in obesity with paradoxical improved outcomes. This phenomenon was previously reported in melanoma patients on immunotherapy; however, results are uncertain. Immune checkpoint inhibitors (ICI) are the mainstay of melanoma treatment. There is a lack of real-world data on the impact of body mass index (BMI) on overall survival (OS) and immunotherapy-related adverse events (irAEs) in melanoma patients on ICI. Methods: Data were retrospectively collected from an electronic health record database (TriNetX) which includes over 89 million patients from 56 healthcare systems in the United States. We identified adults with melanoma who received ICI; pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab between 2012 and 2022. Patients were stratified based on the WHO body mass index (BMI) classification. Overweight and obese patients were 1:1 propensity score-matched for age, sex, race, and use of ICI, with patients with normal BMI. Results: Ourcohort included 11,656 melanoma patients on ICI. 62% were males, 91% were white, and 86% were non-Hispanics. OS was significantly improved in overweight and obese compared to normal BMI patients (HR 0.72, 95% CI, 0.60-0.86; P < 0.001, and HR 0.53, 95% CI, 0.43-0.65); P < 0.001, respectively). Nearly one-third of all weight categories had an irAE. Skin toxicity was the most common, 16.5%-18.2%, while pneumonitis was the least common, 1.0% -2.0%. There was no statistically significant difference between the groups in all included irAE; skin toxicities, thyroid dysfunction, colitis, pneumonitis, or hepatitis. Conclusions: This is the largest real-world data study describing the association between weight status and the outcomes of ICI in melanoma. Our study showed that overweight and obese melanoma patients treated with single or combination ICI had a significantly improved OS compared to patients with normal BMI, in keeping with the “obesity paradox” phenomenon. Intriguingly, high BMI wasn’t associated with an increased risk of irAE. Studies to clarify the underlying mechanisms in melanoma and other malignancies are needed. [Table: see text]