California Cancer Associates for Research and Excellence

Introdução: O diabetes mellitus, em rápida ascensão global, inclui várias formas, como DM1, DM2 e diabetes autoimune latente em adultos (LADA). O LADA, estimado em 3% a 11% da população diabética, foi reconhecido oficialmente pela OMS em 2019 e classificado como um subtipo de DM1 em 2022. Com características genéticas do DM1 e manifestações do DM2, o LADA é frequentemente confundido com DM2, dificultando o diagnóstico e tratamento adequados. Objetivo: Este estudo visa discutir os principais métodos de tratamento do LADA, contribuindo para o conhecimento e aprimoramento das estratégias terapêuticas para essa forma específica de diabetes autoimune. Metodologia: Foi realizada uma revisão integrativa da literatura com busca nas bases de dados PubMed e Cochrane. Foram selecionados 10 artigos que atendiam critérios como publicação nos últimos cinco anos, metodologia rigorosa e relevância para o manejo terapêutico do LADA. Os artigos foram analisados e discutidos em seus principais aspectos. Resultados e Discussão: O tratamento do LADA foca em retardar a apoptose das células beta pancreáticas e melhorar o controle metabólico. A insulina, além de regular a glicemia, tem propriedades imunomoduladoras que protegem as células beta. Inibidores da DPP-4, como sitagliptina, em combinação com vitamina D, mostraram-se promissores em retardar a progressão da doença. Além disso, abordagens emergentes, como a modulação da resposta autoimune pelo anticorpo GADA e intervenções na microbiota intestinal, são áreas de crescente interesse, mas requerem mais investigação. Outras terapias, como GLP-1RAs e SGLT2is, têm mostrado potencial, embora ainda não amplamente estudadas no contexto do LADA. Conclusão: A falta de padronização no tratamento do LADA dificulta o manejo eficaz. No entanto, o uso de insulina, inibidores da DPP-4 e vitamina D demonstra eficácia. Estudos adicionais são necessários para explorar novas terapias e estratégias preventivas para melhorar o tratamento do LADA.

2603 Background: Myeloid cells contribute to suppression of adaptive immunity within the TME and limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Semaphorin 4D (SEMA4D) signaling through its receptors (PlexinB1/B2, CD72) promotes recruitment and suppressive function of myeloid suppressor cells (MDSC). In preclinical and clinical studies, SEMA4D antibody blockade attenuated MDSC and increased penetration and organization of dendritic cells (DC) and T cells into tertiary lymphoid structures that enhanced activity of ICI. We hypothesize that SEMA4D blocking antibody pepinemab may regulate infiltration and crosstalk of immune cells in TME as a novel and complementary mechanism of immune enhancement when combined with immune checkpoint therapy. Methods: KEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of recurrent or metastatic HNSCC. Exploratory biomarker analyses were performed to evaluate spatial interactions of tumoral immune cells. Pre- and on-treatment tumor biopsies were collected and assessed by multiplex immunohistochemistry for up to 36 biomarkers/biopsy. Unbiased algorithms identified co-localization of markers for advanced cell phenotyping, density, spatial and proximity analysis. Biomarker results were then stratified by demographic and clinical outcome measures. Results: An increase in activated APC (HLA-DR+CD11c+ and HLA-DR+CD68+) and reduced density of MDSC (Arg1+CD14+ and ARG1+CD15+) was observed in patients with durable disease control. Interestingly, spatial analysis of tumor biopsies revealed that combination therapy induced the formation of highly organized immune aggregates, including a high density of activated B cells, DCs, CD4+ and CD8+ T cells, including stem-like CD8+TCF1+PD1+ T cells. Presence of immune aggregates increased in on-treatment compared to pre-treatment biopsies, even in HPV-negative and PD-L1 low tumors. Favorable spatial interactions between DC-1, CD8, CD4, and B cells was associated with PFS and disease control. Conclusions: Results suggest that combination therapy induced formation of highly organized lymphoid aggregates in HNSCC tumors, with a high density of activated B cells, DC and T cells. Together with similar observations indicating that combination immunotherapy with pepinemab induces mature lymphoid structures in tumors of patients with metastatic melanoma, provides evidence of treatment-induced biologic activity corresponding with disease control and suggests a novel and independent mechanism of pepinemab to enhance immune interactions and ICI activity. Clinical trial information: NCT04815720 .

BackgroundImmunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) reverses immunosuppression, including attenuation of MDSC recruitment and function1 and promotes organization of lymphoid aggregates within tumors,2 leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination with avelumab was well tolerated and provided clinical benefit in patients with ICI-resistant, PD-L1-low NSCLC.3 The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will improve the efficacy of immunotherapy in R/M HNSCC.MethodsKEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. The study includes immunotherapy naïve patients who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20 with an interim analysis when 36 patients complete the first tumor response assessment. The primary efficacy endpoint is ORR, and secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies are collected for evaluation of immune contexture in TME. Data presented here include pre-specified interim analysis of safety, efficacy, and biomarker assessments.ResultsThe combination appears to be well tolerated with no DLTs observed or safety signals identified by the SMC. Notably, in the PD-L1 low population (CPS<20, N=19), we observed approximately a doubling in ORR, DCR, and PFS for the combination of pepinemab and pembrolizumab, as compared to reported single agent pembrolizumab.4 Among the CPS<20 population, ORR was 21.1% (2 CR and 2 PR), DCR was 73.7%, and median PFS was 5.79 months. In contrast, in the CPS≥20 subgroup, the ORR was 17.6% (n=17), similar to ICI monotherapy for this population. Spatial multiplex IHC analysis of pre- and post-treatment tumor biopsies demonstrated an increase in activated APC, reduced recruitment of MDSC, and highly organized immune aggregates (figure 1) that corresponded with disease control.ConclusionsThe pre-specified interim analysis of the ongoing KN-B84 study showed that pepinemab in combination with pembrolizumab was well-tolerated, suggested early signs of improved anti-tumor response over single agent pembrolizumab in the difficult to treat PD-L1 low group, and provided evidence of treatment-induced biomarker changes in the TME of responder tumors, including formation of high-density lymphoid aggregates.ReferencesClavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Cancer Immunol Res. 2019 Feb;7(2):282–291. doi: 10.1158/2326–6066.CIR-18–0156.Olson B, Mallow C, Reilly C, et al. Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0613Shafique MR, Fisher TL, Evans EE, et al. A Phase Ib/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021, doi: 10.1158/1078–0432.CCR-20–4792Burtness B, Rischin D, Greil R, Soulières D, Tahara M, et al. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321–2332. doi: 10.1200/JCO.21.02198.Ethics ApprovalThis study was approved by WIRB Copernicus Group’s Ethics Board; approval number 20210250. 676 Figure 1Treatment induced improved balance of activated APC and MDSC and presence of highly organized immune aggregates consisting of high density of B cells, DC and T cell zones, and stem- like CD8, and correlate with disease control. (A, B) Representative images of on-treatment biopsies. (C) B cell density/aggregate, each dot represents one aggregate. CR: complete response SD: stable disease, PD: progressive disease.

223 Background: The current standard of care for men with intermediate- and high-risk localized prostate cancer treated with radiotherapy (RT) is the addition of androgen deprivation therapy (ADT). Presently, there are no validated predictive biomarkers to guide ADT use or duration in such men. Herein, we train and validate the first predictive biomarker for ADT use in prostate cancer using multiple phase III NRG Oncology randomized trials. Methods: Pre-treatment biopsy slides were digitized from five phase III NRG Oncology randomized trials of men receiving RT with or without ADT. The training set to develop the artificial intelligence (AI)-derived predictive biomarker included NRG/RTOG 9202, 9413, 9910, and 0126, and was trained to predict distant metastasis (DM). A multimodal deep learning architecture was developed to learn from both clinicopathologic and digital imaging histopathology data and identify differential outcomes by treatment type. After the model was locked, an independent biostatistician performed validation on NRG/RTOG 9408, a phase III randomized trial of RT +/- 4 months of ADT. The DM rates were calculated using cumulative incidence functions in biomarker positive and negative groups, and biomarker-treatment interaction was assessed using Fine-Gray regression such that death without DM was treated as a competing event. Results: Clinical and histopathological data was available for 5,654 of 7,957 eligible patients (71.1%). The training cohort included 3,935 patients and had a median follow-up of 13.6 years (IQR [10.2, 17.7]). After the AI-derived predictive ADT classifier was trained, it was validated in NRG/RTOG 9408 (n = 1719, median follow-up 17.6 years, IQR [15.0, 19.7]). In the NRG/RTOG 9408 validation cohort that had digital histopathology data, ADT significantly improved DM (HR 0.62, 95% CI [0.44, 0.87], p = 0.006), consistent with the published trial results. The biomarker-treatment interaction was significant (p-value = 0.0021). In patients with AI-biomarker positive disease (n = 673, 39%), ADT had a greater benefit compared to RT alone (HR 0.33, 95% CI [0.19, 0.57], p &lt; 0.001). In the biomarker negative subgroup (n = 1046, 61%), the addition of ADT did not improve outcomes over RT alone (HR 1.00, 95% CI [0.64, 1.57], p = 0.99). The 15-year DM rate difference between RT versus RT+ADT in the biomarker negative group was 0.3%, vs biomarker positive group 9.4%. Conclusions: We have successfully validated in a phase III randomized trial the first predictive biomarker of ADT benefit with RT in localized intermediate risk prostate cancer using a novel AI-derived digital pathology-based platform. This AI-derived predictive biomarker demonstrates that a majority of patients treated with RT on NRG/RTOG 9408 did not require ADT and could have avoided the associated costs and side effects of this treatment.

BackgroundCoronavirus disease 2019 (COVID-19) is a global health crisis. The literature suggests that cancer patients are more prone to be affected by COVID-19 because cancer suppresses the immune system and such patients usually present poor results. The objective of this study is to present all clinical, laboratory, and demographic characteristics of COVID-19 patients with solid tumors.MethodologyThis study was conducted at the Dow University of Health Sciences for a period of six months from April 2020 to September 2020. In this study, we included a total of 1,519 confirmed patients diagnosed with solid tumors via polymerase chain reaction. The mortality timeline within 30 days of contracting the virus was considered, and the median age of the included individuals was 61 years, with a range of 20-95 years. Of the patients included in the study, 49.4% (750) were men; moreover, 3.15% of our study population had prostate cancer, 10.20% had colorectal cancer, 2.76% had breast cancer, and 10.46% had lung cancer. Of the patients, 25.93% presented with at least one comorbidity. For 73% of the patients, at least one direct therapy for COVID-19 was included in the treatment; 56.6% of the patients were hospitalized, and 11.32% were admitted to the intensive care unit.ResultsThe mortality rate was 4.74% in the first 30 days after diagnosis, where 72 patients died. The findings of the first multi-variation model showed that males at older ages who were diabetic and going through cytotoxic therapy were prone to die within the first 30 days. However, the 30-day mortality rate was lower in patients diagnosed with prostate and breast cancer. The second set incorporated laboratory factors, where we found that higher values of leukocytosis, thrombocytopenia, and lymphocytopenia were correlated with higher rates of mortality within 30 days.ConclusionsWe conclude that there is a higher mortality rate of COVID-19 in patients with solid tumors than in the general population. However, it was found to be lower in the Pakistani population compared with the Chinese and Western populations. Intensive care can decrease mortality rates in COVID-19 and cancer patients.

IntroductionAvelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC).MethodsIn a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsOverall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred.ConclusionAvelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study.Trial registration detailsClinicalTrials.gov NCT01772004; registered January 21, 2013.

Prostate-specific membrane antigen (PSMA) is awell-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Abstract Background: TGF-β pathway dysregulation may play a critical role in carcinogenesis and immune evasion in HPV-associated cancers (HACs), including anal, cervical, and p16+ squamous cell carcinoma of the head and neck (SCCHN). Targeting this pathway may also enhance clinical response to PD-(L)1 antibodies. M7824 is an innovative first-in-class bifunctional fusion protein composed of two extracellular domains of TGF-βRII (a TGF-β “trap”) fused with a human IgG1 monoclonal antibody against PD-L1. In the dose-escalation cohort of the ongoing Phase I trial of M7824 (NCT02517398), patients with HACs who developed an HPV-specific immune response on M7824 had improved clinical responses. Here we report efficacy and safety data from patients with HPV-positive malignancies from the dose-escalation cohort pooled with data from HAC expansion cohorts for patients with HPV-positive disease. Methods: Patients received M7824 Q2W at 1-30 mg/kg in the dose-escalation phase or at the recommended phase 2 dose of 1200 mg in the expansion cohorts. Treatment continued until progressive disease (PD), unacceptable toxicity, or trial withdrawal; treatment past PD was allowed if clinically justified. Safety and best overall response by RECIST v1.1 were the primary endpoints of the dose-escalation and expansion phases, respectively. Results: As of August 24, 2018, 36 patients with pretreated HPV-positive HACs (4 anal; 18 cervical; 14 SCCHN) had received M7824 for a median duration of 19.0 weeks (range, 2.0-96.0). 10 patients had a response per investigator (2 complete response [CR]; 8 partial response [PR]; ORR 27.8%). 1 additional patient developed a PR after data cutoff; 3 additional patients had a delayed PR after initial PD (total clinical response rate 38.9%). Both patients with CR and 5 patients with PR have an ongoing response. The median duration of response was not reached (range, 4-22+ months). 9 patients (25%) had grade 3 treatment-related adverse events (TRAE): anemia, cystitis, diabetic ketoacidosis, increased γ-glutamyltransferase, gastroparesis, hyperkeratosis, hypokalemia, keratoacanthoma, macular rash, pleural effusion, pneumonitis, and skin SCC. The patient with gastroparesis had asymptomatic grade 3→4 hypokalemia (1 grade 4 TRAE, 2.7%). No treatment-related deaths occurred. 6 patients (16.7%) permanently discontinued M7824 due to TRAEs (gastroparesis, infusion-related reaction, cystitis, pneumonitis, and acneiform and psoriasiform dermatitis). Conclusions: M7824 has a manageable safety profile and shows encouraging clinical efficacy in patients with HPV-positive HACs (total clinical response rate 38.9%). M7824 is a promising therapeutic agent for these patients and is under further evaluation in phase 1b and 2 trials. Updated survival results will be reported. Citation Format: Julius Strauss, Margaret E. Gatti-Mays, Byoung Cho, Sébastien Salas, Edward McClay, Jason Redman, Houssein Abdul Sater, Renee N. Donahue, Elizabeth Lamping, Andrea Burmeister, Jennifer L. Marté, Lisa Cordes, Laureen S. Ojalvo, Christoph Helwig, Alex Rolfe, Christian S. Hinrichs, Ravi A. Madan, Jeffrey Schlom, James Gulley. Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT075.

This randomized, open‐label, active‐controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long‐acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 μg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to <1.5 × 109/L. Up to four cycles of TC were investigated. The difference in DSN (time from ANC <0.5 × 109/L to ANC recovery ≥2.0 × 109/L) between the Rolontis and pegfilgrastim groups was −0.28 days (confidence interval [CI]: −0.56, −0.06) at 270 μg/kg, 0.14 days (CI: −0.28, 0.64) at 135 μg/kg, and 0.72 days (CI: 0.19, 1.27) at 45 μg/kg. Noninferiority to pegfilgrastim was demonstrated at 135 μg/kg (P = 0.002) and 270 μg/kg (P < .001), with superiority demonstrated at 270 μg/kg (0.03 days; P = 0.023). The most common treatment‐related adverse events (AEs) were bone pain, myalgia, arthralgia, back pain, and elevated white blood cell counts, with similar incidences across groups. All doses of Rolontis were well tolerated, and no new or significant treatment‐related toxicities were observed. In Cycle 1, Rolontis demonstrated noninferiority at the 135 μg/kg dose and statistical superiority in DSN at the 270 μg/kg dose when compared to pegfilgrastim.

BackgroundDespite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient’s mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA.MethodsShort-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections.ResultsForty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination.ConclusionsThis is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine.Trial registrationClinical trials.gov NCT00948480 retrospectively registered 28 July 2009.