Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.

BACKGROUND: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER: NCT04047290.

Enhancing Checkpoint Inhibitor Therapy in Solid Tissue Cancers: The Role of Diet, the Microbiome & Microbiome-Derived Metabolites.

Host immunity plays a central role in the regulation of anti-tumour responses during checkpoint inhibitor therapy (CIT). The mechanisms involved in long lasting remission remain unclear. Animal studies have revealed that the microbiome influences the host immune response. This is supported by human studies linking a higher microbial richness and diversity with enhanced responses to CIT. This review focuses on the role of diet, the microbiome and the microbiome-derived metabolome in enhancing responses to current CIT in solid tissue cancers. The Western diet has been associated with dysbiosis, inflammation and numerous metabolic disorders. There is preliminary evidence that lifestyle factors including a high fibre diet are associated with improved responses to CIT via a potential effect on the microbiota. The mechanisms through which the microbiota may regulate long-term immunotherapy responses have yet to be determined, although bacterial-metabolites including short chain fatty acids (SCFAs) are recognized to have an impact on T cell differentiation, and may affect T effector/regulatory T cell balance. SCFAs were also shown to enhance the memory potential of activated CD8 T cells. Many therapeutic approaches including dietary manipulation and fecal transplantation are currently being explored in order to enhance immunotherapy responses. The microbiome-derived metabolome may be one means through which bacterial metabolic products can be monitored from the start of treatment and could be used to identify patients at risk of poor immunotherapy responses. The current review will discuss recent advances and bring together literature from related fields in nutrition, oncology and immunology to discuss possible means of modulating immunity to improve responses to current CIT.

Therapeutic implications of immune-profiling and EGFR expression in salivary gland carcinoma.

BACKGROUND: Data relating to the efficacy of immune checkpoint inhibitors (ICI) for salivary gland carcinomas (SGC) is gradually evolving with responses varying among different histotypes. To address these disparities, this retrospective analysis examined the prevalence of recognized biomarkers of response to ICI; namely programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), combined positive score (CPS), epidermal growth factor receptor (EGFR), and microsatellite instability (MSI) in patients with SGC with an aim to determine any prognostic or survival benefits and stratify the use of ICI in this disease. PATIENTS AND METHODS: Of 52 patients with primary SGC eligible for this study, the most common histological types were adenoid cystic carcinoma (n = 17, 33%), salivary duct carcinoma (n = 14, 27%), mucoepidermoid carcinoma (n = 11, 21%), and acinic cell carcinoma (n = 6, 11%). Immunohistochemistry (IHC) was performed using the Ventana Discovery Ultra auto-staining platform for EGFR, PD-1, PD-L1, and mismatch repair (MMR) proteins. CPS ≥1 defined PD-L1 positive cases and log-rank testing was performed to examine the relationship between PD-L1 expression status and disease-free survival (DFS) and overall survival (OS). RESULTS: CPS positivity was seen in 9 (17.3%) patients, none of which were adenoid cystic carcinoma. All 52 (100%) cases expressed retained MMR proteins inferring microsatellite stability (MSS) and EGFR expression was identified in 45 of 52 (86.5%) patients. CPS positivity (score ≥1) was significantly associated with advanced pathological T status (P = .021), advanced pathological N status (P = .006), high histological tumor grade (P = .045), and positive histological margin (P = .023). Patients with PD-L1 positivity in tumor cells did not have an inferior 3-year OS (P = .93). CONCLUSION: The data from this retrospective study highlighting the uniform microsatellite stability alongside the low prevalence of CPS positivity suggests that only a minority of SGC patients may benefit from ICI therapy alone. The high rates of EGFR expression in SGC may be a target to augment immune checkpoint therapy response.

L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution.

LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent in vitro and in vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity.

Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies.

The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents.

Mucinous ovarian cancer: A therapeutic review.

Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering 'GI style' chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations.

The role of interleukin-6 in malignant mesothelioma.

Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival.

Interleukin-6: an angiogenic target in solid tumours.

During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.

Chemotherapy advances in small-cell lung cancer.

Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms.

The role of interleukin-6 in gynaecological malignancies.

There are many parallels between gynaecological cancers in relation to cytokine networks within their respective tumour microenvironments and evidence to support interleukin-6 (IL-6) being an appropriate therapeutic target in these diseases. This article provides an overview on IL-6 biology including updates on novel discoveries in IL-6 signalling and then focuses on the role of IL-6 in processes such as cell proliferation, migration, angiogenesis, evasion of tumour immunity and chemoresistance and presents data relating to the abrogation of these processes with anti-IL-6 targeted therapy in preclinical and clinical studies. The overall aim will be to highlight the necessity for further translational studies concentrating on combinations of anti-IL-6/IL-6R therapies with other novel targets in an attempt to significantly improve overall survival in patients with gynaecological cancers.

True hypoglycaemia secondary to treatment with granulocyte colony stimulating factor (G-CSF) in a diabetic patient with non-small cell lung cancer.

We report the case of a 61-year-old man with non-small lung cancer with poorly controlled type 2 diabetes mellitus who developed clinically significant hypoglycaemia secondary to a first exposure to granulocyte colony stimulating factor (G-CSF) injections. Whilst artefactual hypoglycaemia during treatment with G-CSF is well recognised, to our knowledge, this is the first report revealing that it can provoke true hypoglycaemia in the absence of leucocytosis.

Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report.

This case report focuses on an elderly gentleman with extensive stage small cell lung cancer (SCLC) who experienced episodes of bowel obstruction shortly after commencing first-line chemotherapy with cisplatin and etoposide. The patient had no radiological or pathological evidence of intra-abdominal carcinomatosis or paraneoplastic bowel disease secondary to SCLC. Although neurotoxicity is commonly associated with platinum agents, the effect is predominantly peripheral as opposed to autonomic. The authors conclude that the observations documented in this case were secondary to etoposide; a podophyllotoxin that can bind microtubules and inhibit fast axonal transport. Although paralytic ileus is well recognised with podophyllotoxin poisoning, to our knowledge, this is the first report to associate bowel obstruction with standard doses of etoposide and highlights the need for physicians to be aware of such deleterious effects in patients treated with this cytotoxic agent.