Received Combination Treatment Research Articles

Abstract A004: A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma

Abstract Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is recalcitrant to approved immunotherapies. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Furthermore, preclinical studies suggest that monoclonal blockade of SEMA4D supports CD8+T cells tumoral infiltration and activation, sensitizing PDAC to immune checkpoint blockade (ICB). Thus, we hypothesized that a humanized anti-SEMA4D antibody (pepinemab) may improve disease control and responsiveness to ICB in patients with PDAC. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of pepinemab with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC (NCT05102721). The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval design targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. Results: A total of 14 patients have been enrolled to date. Three subjects withdrew from the study prior to completing the evaluable period (four weeks of treatment) and nine subjects terminated treatment due to disease progression. Two subjects continue to receive combination treatment pending evaluation of tumor response. Baseline and on-treatment biopsies have been obtained and stored for correlative analysis from 8 evaluable subjects. One treatment-related adverse event occurred though the patient was able to complete treatment without further events. No treatment-related toxicities have been encountered. Conclusions: Combining pepinemab with avelumab appears to be safe and tolerable to date. Nine of eleven patients demonstrated disease progression, though 1 of these 9 demonstrated mixed response with some lesions showing radiologic partial and even complete response. Overall treatment response, survival data, and correlative science forthcoming. Citation Format: Luis I Ruffolo, Matthew Byrne, Bailey Hilty, Brian A Belt, Yatee Dave, Paul Burchard, Terrence Fisher, Elizabeth E. Evans, Crystal Mallow, Megan Boise, Darren Carpizo, Jen Jen Yeh, David C Linehan, Daniel Mulkerin. A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A004.

Clinical predictive factors of the efficacy of immune checkpoint inhibitors and kinase inhibitors in advanced hepatocellular cancer.

Hepatocellular carcinoma (HCC) is a highly aggressive tumor associated with significant morbidity and mortality rates. Combination therapy with immune checkpoint inhibitors (ICIs) and kinase inhibitors has emerged as a promising strategy for liver cancer treatment in recent years. However, the clinical factors predicting the outcomes of combination therapy in patients with advanced liver cancer remain uncertain. Therefore, this study investigated the relationships between clinical predictors and the efficacy of ICI plus kinase inhibitor therapy to personalize treatment plans. We retrospectively enrolled 98 patients who received combination treatment with ICIs and kinase inhibitors for advanced HCC. Based on blood lipid levels and other clinical factors prior to treatment, we investigated potential biomarkers that could predict treatment responses in this patient population. Mean progression-free survival (PFS) and overall survival (OS) in this cohort were 10.1 and 17.2months, respectively. Via multivariate analysis, the absence of extrahepatic metastasis, the absence of portal vein thrombosis (PVT), neutrophil-to-lymphocyte ratio (NLR) < 3.225, platelet-to-lymphocyte ratio (PLR) < 140.75, and prognostic nutritional index (PNI) ≥ 37.25 were identified as independent predictors of improved PFS. Factors associated with better OS included PLR < 140.75 and total cholesterol (TC) < 3.46mmol/L. Univariate analysis identified significant associations of Eastern Cooperative Oncology Group performance status (ECOG PS), hepatitis B virus (HBV) DNA levels, Child-Pugh classification, alpha-fetoprotein (AFP), TC, and the receipt of regorafenib with PFS. Additionally, ECOG PS, Child-Pugh classification, AFP, PVT, NLR, PNI, and the receipt of regorafenib were significantly associated with OS. PLR and TC were potential clinical predictive factors for survival outcomes in patients with advanced HCC who received ICI/kinase inhibitor combination therapy. It is important to know the clinical characteristics of patients prior to treatment initiation to optimize outcomes.

Clinical, Genomic, and Transcriptomic Characteristics of Patients with Metastatic Renal Cell Carcinoma Who Developed Thromboembolic Events.

Thromboembolic events (TE) are a common complication in patients with metastatic renal cell carcinoma (mRCC) and are associated with poorer clinical outcomes. However, the incidence of TE and clinical and genomic characteristics of patients with mRCC who develop this complication are poorly understood. Herein, we describe the incidence and clinical features of patients with mRCC with or without TE at our institution, and examine their association with the underlying genomic and transcriptomic characteristics of the tumor. This retrospective study included all consecutive cases of mRCC seen at our institution. A CLIA-certified lab performed tumor genomics and transcriptomics. Patients were classified based on the presence of a TE within the first year of diagnosis. Three hundred and seventy patients with mRCC were included in the study. TE was seen in 11% (42) of the patients. Patients with favorable International mRCC Database Consortium (IMDC) risk were less likely to develop a TE. In contrast, patients receiving combination treatment with a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor were more likely to develop a TE. No difference in overall survival among patients with or without TE was observed (52 vs. 55 months; HR 0.85, 95% CI 0.5574-1.293, p = 0.24). The most upregulated pathways in mRCC with TEs versus those without were the xenobiotic metabolism and mTORC1 signaling pathways. Our findings suggest potential biomarkers that, after external validation, could be used to better select patients who would benefit from prophylactic anticoagulation.

NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma.

Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting. The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results. Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively. IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM. NCT02311920.

Retrospective Large Database Study of Central Serous Chorioretinopathy Treatments and Visual Outcomes Analysis in the United States.

Purpose: To evaluate a large database detailing the changes in visual acuity (VA) and central subfield thickness after various treatments for central serous chorioretinopathy (CSCR). Methods: A retrospective analysis was performed of patients with CSCR from January 2015 to September 2022 using the Vestrum Health Retina Database of aggregated de-identified electronic medical records from retina specialists in the United States. The cases of CSCR were categorized by age, sex, and treatment provided. Results: The annual incidence of CSCR was 1.72% (61 755 of 3 598 672 patient eyes), with a mean patient age of 53 years. Male eyes comprised 71.8% of the patient population. Eighty-five percent of patients received no treatment within 1 year of diagnosis. Of the patients needing treatment, 21% received thermal laser therapy, 23% photodynamic therapy, and 49% antivascular endothelial growth factor (anti-VEGF) intraocular injection. Patients not receiving treatment had the best baseline and 1-year VA. All treatment groups had an increased percentage of patients gaining letters compared with patients not receiving treatment. Conclusions: Although most patients did not require treatment, those who received treatment generally did well, with a large proportion having visual gain. Statistical analysis suggests treatment has a positive impact on VA outcomes. Patients receiving combination treatment were older and had the least visual gain of the treated cohorts. Younger patients with CSCR treated with anti-VEGF (and without a secondary diagnosis of macular degeneration) had the greatest increase in VA at 1 year.

Reconstructive plastic surgery in combined treatment of breast cancer: Predictive risk factors of complications and reconstruction failure.

e12594 Background: Breast reconstruction after mastectomy must consider potential complications from surgical techniques as well as additional complications of oncologic treatment such as radiation or systemic therapy. But the consensus is lacking regarding the optimal reconstruction plan for patients requiring adjuvant radiation therapy. Objective: To determine the impact of risk factors on the development complications of breast reconstruction for postmastectomy radiotherapy. Methods: This study included patients diagnosed with breast cancer who received combination treatment from 2016 to 2021 at the FSBI “N.N. Petrov National Medical Research Center of Oncology” of the Russian Ministry of Health. The patients were divided into 3 groups: immediate reconstruction (158 people), immediate-delayed (210 people) and delayed (98 people). Results: Every fourth patient (24.0%, 112/466) may encounter a complication after mastectomy with reconstruction and adjuvant radiation therapy. According to the analyzed data, there was no correlation between potential risk factors depending on the general status of patients (age, obesity, diabetes mellitus, hypertension, history of smoking) and the occurrence of complications after combination treatment. Conclusions: The analysis of complications and reconstructive failures showed that immediate breast reconstruction at the FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Health of Russia is the safest method of reconstruction in the combined treatment of breast cancer with the lowest incidence of severe complications (9.5%, 15/158, z&gt;1.96), which plays a key role in the development of reconstructive failures (Pearson Correlation=0.861, p&lt;0.001). However, these surgeries are associated with a significant number of capsular contractures (15.2%, 24/158, z&gt;1.96, Pearson Correlation=0.230, p&lt;0.001), which requires finding ways to minimize these risks to optimize treatment in each individual case in short and long term results.

Efficacy and safety of anlotinib combined with sintilizumab in locally advanced or metastatic anaplastic thyroid carcinoma.

6103 Background: Anaplastic thyroid carcinoma (ATC) is rare aggressive and fatal malignancy with poor prognosis. Antiangiogenic and multikinase inhibitors and programmed cell death protein-1 (PD-1) antibodies have conferred benefits for ATC. We aimed to assess the efficacy and safety of anlotinib plus sintilizumab in patients with locally advanced or advanced ATC. Methods: In this prospective study, patients with histologically confirmed locally advanced or metastatic ATC, received a combination therapy of anlotinib and sintilizumab. Anlotinib was started at 12 mg once daily for 14 days and combined with sintilizumab at a fixed dose of 200 mg every three weeks. The primary end point was objective response rate (ORR), assessed in patients who received at least one dose of treatment. Tumor samples were characterized by next-generation sequencing in 12 patients and PD-L1 expression levels in 14 patients. Results: Between June 1st, 2022 and August 21st, 2023, 18 patients with locally advanced or metastatic ATC were enrolled and received combination treatment. Best overall response (BOR) within all patients was 5.6% (1/18) complete remission, 38.9% partial remission (7/18), 33.3% stable disease (6/18), and 22.2% progressive disease (4/18). ORR was 44.4% for all patients and 80.0% for 5 patients with BRAF V600E mutation. The only one patient with PD-L1 negative also reached PR. Median follow up time was 14.6 months for all patients and 16.1 months for patients with BRAF V600E mutation. The median progression-free survival was 7.5 months (0.5 to 56.3 months) for all patients and 5.7 months (1.0 to 13.1 months) for patients with BRAF V600E mutation. Duration of treatment was 5.9 months (0.5 to 38.2 months), and 8 of 18 ATC patients are still on therapy. Grade III/IV toxicities were observed in 4 of 18 patients, necessitating dose reduction/discontinuation of anlotinib. The 1-year overall survival (OS) rate was 61.1% and median OS was 12.9 months (0.6 to 56.3 months), with 8 ATC patients being still alive without progression. Conclusions: The combination of anlotinib and sintilizumab demonstrated promising activity and manageable toxicity in patients with locally advanced or metastatic ATC, suggesting its potential as a viable therapeutic option for this patient population. Clinical trial information: ChiCTR2200067045. [Table: see text]

Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Preliminary results of cohort 1 of the phase 1 LITESPARK-010 study.

4537 Background: Belzutifan, a first-in-class HIF-2α inhibitor, alone or in combination with a VEGFR-TKI, has shown durable antitumor activity in first- and subsequent-line settings of advanced ccRCC. LITESPARK-010 (NCT05030506) is a phase 1, 2-cohort, open-label study of belzutifan + len, with or without pembrolizumab, in Chinese pts with advanced ccRCC. We present preliminary results cohort 1. Methods: Chinese adults with histologically confirmed ccRCC who had 1-3 prior treatment regimens received belzutifan 120 mg PO QD for 3 wk followed by belzutifan 120 mg + len 20 mg PO QD until intolerable toxicity, disease progression, or pt withdrawal. The study included a dose-limiting toxicity (DLT) phase of 21 days after the start of combination treatment. Dual primary end points were safety and PK. Secondary end points included ORR, DOR, and PFS per RECIST v1.1 by investigator assessment and OS. Results: As of August 29, 2023, 24 pts were enrolled in cohort 1 and 23 received combination treatment; 1 pt discontinued in the monotherapy period because of treatment with non-study anti-cancer therapy. Median age was 61 years, 17 pts (71%) were male, and 14 (58%) had intermediate/poor IMDC risk. 14 pts (58%) received 1 prior line of therapy and 10 (42%) received ≥2 prior lines. Five pts (21%) received prior therapy with a PD-(L)1 inhibitor. As of the data cutoff date, 11 pts (46%) remained on treatment. Median follow up was 14.4 mo (range, 1.6-22.1). Ten pts were evaluated in the DLT phase, and 1 experienced a DLT (grade 2 treatment-related transient ischemic attack). All 24 pts (100%) experienced a treatment-related AE (TRAE) of any grade, most commonly anemia (100%) and proteinuria (88%). Grade 3 or 4 TRAEs occurred in 17 pts (71%), most commonly anemia (29%) and hypertension (29%). One pt (4%) experienced grade 3 hypoxia. No pts died (grade 5) due to a TRAE. After a single dose of belzutifan monotherapy, median Tmax was 1.8 h (range, 0.6-8.0), geometric mean AUC0-24 was 22,400 h·ng/mL (90% CI, 19,600-25,500), and geometric mean Cmax was 1640 ng/mL (90% CI, 1490-1820). Steady-state concentration was reached after 14 days of belzutifan monotherapy treatment; the accumulation ratio of AUC0-24 was 1.7 (90% CI, 1.5-1.9). Belzutifan + len treatment had similar PK to belzutifan monotherapy. In all 24 pts, confirmed ORR was 50% (95% CI, 29-71; all PRs). Median DOR was not reached (NR; range, 3.5-20.4+ months); 50% of responders remained in response for ≥12 mo per Kaplan-Meir estimate. Median PFS was 13.7 mo (95% CI, 8-NR) and median OS was NR (95% CI, NR-NR). The 12-mo PFS and OS rates were 57% and 75%, respectively. Conclusions: Preliminary data from the belzutifan + len showed promising antitumor activity in Chinese pts with previously treated ccRCC. The safety of belzutifan 120 mg + len 20 mg was consistent with the safety profiles of the individual drugs. Clinical trial information: NCT05030506 .

Depression and Anxiety in Cancer Patients at a Tertiary Care Center in Central India

ABSTRACT Background and Objectives: Cancer is a life-threatening disease which can also lead to mental health issues such as depression and anxiety, which add to the burden of illness in cancer patients. This study aimed to describe the prevalence and risk factors of depression and anxiety among cancer patients during treatment. Materials and Methods: A total of 128 patients were included in the study. The prevalence of depression and anxiety in patients was assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scale. A cutoff score of ten or more was set to diagnose depression and anxiety, respectively. Various risk factors associated with depression and anxiety were assessed. Results: The prevalence of depression and anxiety in cancer patients was 31.25% and 15.62%, respectively. The prevalence of depression was most common in head-and-neck cancer and ovarian cancer, while the prevalence of anxiety was most common in head-and-neck cancer and lung cancer. The prevalence of both depression and anxiety was higher in stage IV versus stage III, in males versus females, and in the age group of 41–50 years. The patients receiving chemotherapy had a higher prevalence compared to those receiving combination treatment. Conclusion: Our study demonstrated a high prevalence of depression and anxiety in cancer patients during cancer treatment which is affected by a variety of factors. It highlights the problem of psychiatric burden in cancer patients and the need to address this problem by improving means for the early detection and early administration of treatment.

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA

Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. Merck Sharp & Dohme.

Effectiveness of combined first-line medical treatment in acromegaly with prolactin cosecretion.

The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.

Effectiveness and safety of the ablative fractional 2940-nm Er: YAG laser for the treatment of androgenetic alopecia.

Laser sources have established their potential effect in inducing hair regrowth. No large cohort study has evaluated the effect of ablative fractional 2940-nm erbium yttrium aluminum garnet (Er: YAG) laser in the treatment of androgenetic alopecia (AGA). To investigate the efficacy and safety of the ablative fractional 2940-nm Er: YAG laser in combination with medication therapy for the treatment of AGA. We performed a retrospective study between first July 2021 to 30th December 2021. All included patients received oral finasteride and topical minoxidil, or combined with six sessions of Er: YAG laser at 2-week intervals. Patients were divided into medication or combined therapy groups. The efficacy of the two therapies was evaluated by the investigator's Global Assessment (IGA) scores and the patient's Likert satisfaction scale at week 12 and week 24. Changes in total, terminal and villous hair count, total and terminal hair diameter, and AGA grade were also recorded. Adverse events were evaluated at each follow-up. A total of 192 male patients with AGA were included, including 67 receiving combination treatment, and 125 receiving medication treatment. At week 24, the combination treatment afforded superior outcomes in the IGA score, patient's global assessment, total and terminal hair counts, and diameters (all P<0.05). No severe adverse events were reported in both groups. The combined therapy of ablative fractional Er: YAG laser and medication was superior in treating male AGA than single medication therapy without serious adverse effects.

The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion

As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Abstract 4178: Non-invasive shortwave infrared imaging of cytotoxic T lymphocyte infiltration for monitoring responses to combination immunotherapy and chemotherapy

Abstract Although triple-negative breast cancer (TNBC) can be treated with anti-PD-1 checkpoint immunotherapy in combination with chemotherapy, there remains a challenge in effectively monitoring therapeutic responses. Current non-invasive clinical imaging tools to evaluate response to treatment are reliant upon measurements of tumor volume and may fail to distinguish true progression from increased immune cell infiltration. Invasive biopsy sampling and immunohistochemistry (IHC) can elucidate changes in the immune landscape of treated tumors, but these methods are not conducive to providing real-time information. This study presents shortwave infrared (SWIR) imaging as a potential tool to detect treatment-induced cytotoxic T lymphocyte (CTL) infiltration non-invasively and in real time using rare earth metal-doped nanoparticles encapsulated in human serum albumin nanocomposites (ReANCs). ReANCs were chemically conjugated with anti-CD8α antibodies as targeting ligands to facilitate binding of the nanoprobes to CTLs with high specificity in a syngeneic mouse model of breast cancer. After treating the mice with combination anti-PD-1 and doxorubicin, volumetric analysis of the mammary fat pad tumors did not show any significant impact of treatment compared to single treatment and untreated control mice. However, increased CTL infiltration in the tumors of mice that received combination treatment was detected by in vivo SWIR imaging. CTL infiltration was validated with ex vivo IHC staining, and a monotonic relationship was observed between SWIR fluorescence and CD8 positivity. IHC staining of other immune markers, including CD45, CD3, CD4, and PD-L1, showed that combination treatment may influence in the expression of these markers, presenting additional targets that could be imaged with ReANCs in the future. In conclusion, the increase in SWIR signal from CD8-targeted ReANCs in tumors treated with combination immunotherapy and chemotherapy and the relationship with IHC staining highlight the ability to use SWIR imaging for non-invasive assessment of changes in immune dynamics following treatment. Citation Format: Jay V. Shah, Jake N. Siebert, Xinyu Zhao, Shuqing He, Richard E. Riman, Mei Chee Tan, Mark C. Pierce, Edmund C. Lattime, Vidya Ganapathy, Prabhas V. Moghe. Non-invasive shortwave infrared imaging of cytotoxic T lymphocyte infiltration for monitoring responses to combination immunotherapy and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4178.

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. Patients (n= 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n= 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage2. NCT03812796 (registered 23rd January 2019).

The efficacy of bacteriophage/probiotic combination therapy in periodontal treatment

Relevance. Periodontal inflammations result from chronic, persistent infections triggered by dysbiosis-induced shifts within the microbial community. The high prevalence, multifactorial nature and challenging management of periodontal disease create an environment ripe for ongoing advancements in treatment modalities.Study objective: To validate, using clinical and laboratory test data, the efficacy of combined treatment involving bacteriophages and probiotics in managing chronic periodontitis.Materials and methods. A total of 100 patients aged 18 to 45 with periodontal inflammation underwent clinical laboratory examinations before receiving combination treatment. The patients were divided into two groups: Group 1 received conventional treatment based on clinical recommendations, while Group 2 received sequential treatment with a bacteriophage cocktail (targeting 81 phages against A. actinomycetemcomitans, B. licheniformis, B. fragilis, E. cloacae, E. faecalis, K. pneumonia, S. aureus, S. pyogenes, Wolinella spp. among others) followed by a probiotic containing S. Salivarius. Periodontal pocket lavages served as study material. Periodontal pathogens were isolated using real-time PCR, and proinflammatory cytokines were identified via enzyme immunoassay. Statistical analysis was conducted using STATA v.12 software.Results. Following bacteriophage/probiotic combination treatment, positive changes in study indices and a reduction in periodontopathogenic microbiota were observed. Significant decreases were noted in the levels of key periodontal pathogens: P. gingivalis (5.2-fold decrease, p &lt; 0.001), P. intermedia (3.6-fold decrease, p &lt; 0.001; T. forsythia (3.8-fold decrease, p = 0.905), T. denticola 4-fold decrease, p &lt; 0.001. Levels of IL1-β decreased by factors of 4.29 (p &lt; 0.001) and 8.59 (p = 0.02) in severity subgroups, while IL6 levels decreased by factors of 4.39 (p &lt; 0.001) and 5.94 (p = 0.0002). The lowest TNF-α levels (2.13 in mild CGP subgroup and 2.11 in moderate CGP subgroup) were observed post-treatment (p &lt; 0.001; p = 0.0005).Conclusion. The combination treatment involving the selected drugs exhibited notable therapeutic effectiveness in the management of chronic periodontitis. This approach not only avoided the necessity for systemic antibacterial agents but also facilitated prolonged remission by eradicating periodontopathogenic microbiota in patients with chronic periodontitis. The etiopathogenetic nature of this treatment represents a promising paradigm in the management of periodontal inflammation.

Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial

New obesity medications result in large weight losses. However, long-term adherence in a real-world setting is challenging, and termination of obesity medication results in weight regain towards pre-treatment body weight. Therefore, we investigated whether weight loss and improved body composition are sustained better at 1year after termination of active treatment with glucagon-like peptide-1 (GLP-1) receptor agonist, supervised exercise program, or both combined for 1 year. We conducted a post-treatment study in extension of a randomised, controlled trial in Copenhagen. Adults with obesity (aged 18-65 years and initial body mass index 32-43kg/m2) completed an eight-week low-calorie diet-induced weight loss of 13.1kg (week-8 to 0) and were randomly allocated (1:1:1:1) to one-year weight loss maintenance (week 0-52) with either supervised exercise, the GLP-1 receptor agonist once-daily subcutaneous liraglutide 3.0mg, the combination of exercise and liraglutide, or placebo. 166 Participants completed the weight loss maintenance phase. All randomised participants were invited to participate in the post-treatment study with outcome assessments one year after treatment termination, at week 104. The primary outcome of the post-treatment assessment was change in body weight from after the initial weight loss (at randomisation, week 0) to one year after treatment termination (week 104) in the intention-to-treat population. The secondary outcome was change in body-fat percentage (week 0-104). The study is registered with EudraCT, 2015-005585-32, and with ClinicalTrials.gov, NCT04122716. Between Dec 17, 2018, and Dec 17, 2020, 109 participants attended the post-treatment study. From randomisation to one year after termination of combined exercise and liraglutide treatment (week 0-104), participants had reduced body weight (-5.1kg [95% CI-10.0;-0.2]; P=0.040) and body-fat percentage (-2.3%-points [-4.3 to-0.3]; P=0.026) compared with after termination of liraglutide alone. More participants who had previously received combination treatment maintained a weight loss of at least 10% of initial body weight one year after treatment termination (week-8 to 104) compared with participants who had previously received placebo (odds ratio [OR] 7.2 [2.4; 21.3]) and liraglutide (OR 4.2 [1.6; 10.8]). More participants who had previously received supervised exercise maintained a weight loss of at least 10% compared with placebo (OR 3.7 [1.2; 11.1]). During the year after termination of treatment (week 52-104), weight regain was 6.0kg [2.1; 10.0] larger after termination of liraglutide compared with after termination of supervised exercise and 2.5kg [-1.5 to 6.5] compared with after termination of combination treatment. The addition of supervised exercise to obesity pharmacotherapy seems to improve healthy weight maintenance after treatment termination compared with treatment termination of obesity pharmacotherapy alone. Body weight and body composition were maintained one year after termination of supervised exercise, in contrast to weight regain after termination of treatment with obesity pharmacotherapy alone. Helsefonden and the Novo Nordisk Foundation.

Real-World Use and Effectiveness Outcomes in Patients with Rheumatoid Arthritis Treated with Upadacitinib: An Analysis from the CorEvitas Registry.

Data assessing longer-term real-world effectiveness and treatment patterns with upadacitinib (UPA), a Janus kinase inhibitor, in rheumatoid arthritis (RA) are lacking. We assessed improvement in clinical and patient-reported outcomes and treatment patterns for up to 12months among adult patients with RA initiating UPA. Data were collected from the CorEvitas® RA Registry (08/2019-04/2022). Eligible patients had moderate to severe RA (Clinical Disease Activity Index [CDAI] > 10) and follow-up visits at 6 or 12months after UPA initiation. Outcomes were mean change from baseline, percentage achieving minimal clinically important differences (MCID) in clinical and patient-reported outcomes, and disease activity at follow-up. We evaluated clinical outcomes and therapy changes among patients with tumor necrosis factor inhibitor (TNFi) experience and among those receiving UPA as first-line therapy, as well as those receiving UPA as monotherapy versus as part of combination therapy. We further evaluated whether outcomes were similar among those that remained on therapy. Patients treated with UPA (6-month cohort, N = 469; 12-month cohort, N = 263) had statistically significant improvements (p < 0.001) in mean CDAI, tender/swollen joint counts, pain, and fatigue at follow-up. At 12months, 46.0% achieved MCID in CDAI and 40.0% achieved low disease activity/remission. Overall, 43.0% discontinued UPA at 12months; of those receiving combination treatment (N = 90) with conventional therapies and UPA, 42.2% (N = 38) discontinued conventional therapy. Findings were similar in the 6-month cohort and among subgroups. Changes from baseline and proportions of patients achieving MCID or clinical outcomes tended to be numerically lower among patients with TNFi experience and numerically higher among those receiving UPA as first-line therapy. UPA initiation was associated with improvements in clinical and patient-reported outcomes, with meaningful clinical improvements regardless of prior TNFi experience, line of therapy, or concomitant use of conventional therapies. Further research is needed to better understand sustained response of UPA over longer treatment periods.

P870 Effectiveness and safety of adalimumab as first line biological treatment in Ulcerative Colitis

Abstract Background The increase in licensed therapies for ulcerative colitis (UC) is revolutionizing its treatment but making first line choice more challenging. Adalimumab (ADA) is inexpensive but, anecdotally, is sometimes regarded as less effective than other first line advanced therapies. We aimed to evaluate the results of first line ADA in UC. Methods We performed a single centre retrospective analysis of UC patients started on ADA between January 15 and March 2022 in an IBD referral hospital. Clinical remission was defined as SCCAI &amp;lt;2 points, endoscopic remission as a UCEIS &amp;lt;2 points and treatment failure as the need for colectomy or second biological line Results A total of 79 patients were included (Table 1). Median follow-up was 19 months (2-91); 78.5% were followed &amp;gt;6 months. At 6 months, 80.3% (61/76) and 37.3% (22/59) of the patients were in clinical and endoscopic remission, respectively. 54.3% received combination treatment with immunomodulators (50.6% thiopurines, 3.7% methotrexate). Dose intensification to weekly treatment occurred in 27.8% after median 9 months (4-48 months). During follow-up 51% received corticosteroids at some point (26% topically-acting oral corticosteroids, 10% oral corticosteroids, 15% both). Of patients who received steroids, 55% (22/40) were able to continue adalimumab therapy. 2.5% of patients were hospitalised for a disease flare. 5.1% had an infection recorded during follow up, none discontinued the treatment. No other major adverse events were recorded. In 22.8% (18/79) of patients, ADA was stopped due to treatment failure, mean 15 months after starting the drug (4-56 months), (Figure 1). None of these patients underwent colectomy at the time of stopping the drug; in 17/18 a second biological therapy was started (10 tofacitinib, 1 filgotinib, 1 upadacitinib, 2 ustekinumab, 2 vedolizumab, 1 golimumab). TDM was performed using a drug-sensitive ELISA, which is only able to detect antidrug antibodies when drug levels are low or absent. Drug levels at the time of stopping the drug were &amp;lt;5 µg/mL in 22% of patients (in 2 antibodies were detected), 5-8 µg/mL in 11% and &amp;gt;8 µg/mL in 67%. Conclusion In a real-world UC cohort, ADA appears to be an effective well tolerated first-line advanced therapy with the vast majority of patients reaching clinical remission and a significant proportion achieving mucosal healing. Table 1. Cohort characteristics (N 79, frequency and %). Figure 1: Kaplan-Meier survival analysis of time to ADA discontinuation.

Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 μg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.