Springer Science and Business Media LLC

Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.

Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK-1 was initially found in anaplastic large cell lymphoma (ALCL). ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. Multiple small molecule inhibitors with activity against ALK and related oncoproteins are under clinical development. Two of them, crizotinib and ceritinib, have been approved by FDA for treatment of locally advanced and metastatic NSCLC. More agents (alectinib, ASP3026, X396) with improved safety, selectivity, and potency are in the pipeline. Dual inhibitors targeting ALK and EGFRm (AP26113), TRK (TSR011), FAK (CEP-37440), or ROS1 (RXDX-101, PF-06463922) are under active clinical development.

Additional sex combs-like 1 (ASXL1) is frequently mutated in myeloid malignancies. Recent studies showed that hematopoietic-specific deletion of Asxl1 or overexpression of mutant ASXL1 resulted in myelodysplasia-like disease in mice. However, actual effects of a “physiological” dose of mutant ASXL1 remain unexplored. We established a knock-in mouse model bearing the most frequent Asxl1 mutation and studied its pathophysiological effects on mouse hematopoietic system. Heterozygotes (Asxl1 tm/+ ) marrow cells had higher in vitro proliferation capacities as shown by more colonies in cobblestone-area forming assays and by serial re-plating assays. On the other hand, donor hematopoietic cells from Asxl1 tm/+ mice declined faster in recipients during transplantation assays, suggesting compromised long-term in vivo repopulation abilities. There were no obvious blood diseases in mutant mice throughout their life-span, indicating Asxl1 mutation alone was not sufficient for leukemogenesis. However, this mutation facilitated engraftment of bone marrow cell overexpressing MN1. Analyses of global gene expression profiles of ASXL1-mutated versus wild-type human leukemia cells as well as heterozygote versus wild-type mouse marrow precursor cells, with or without MN1 overexpression, highlighted the association of in vivo Asxl1 mutation to the expression of hypoxia, multipotent progenitors, hematopoietic stem cells, KRAS, and MEK gene sets. ChIP-Seq analysis revealed global patterns of Asxl1 mutation-modulated H3K27 tri-methylation in hematopoietic precursors. We proposed the first Asxl1 mutation knock-in mouse model and showed mutated Asxl1 lowered the threshold of MN1-driven engraftment and exhibited distinct biological functions on physiological and malignant hematopoiesis, although it was insufficient to lead to blood malignancies.

Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0–29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0–10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8–59.8%) and 42.3% (95% CI, 18.8–65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7–12.5) months and 18.3 (95% CI, 12.5–20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3–4 cytokine release syndrome (CRS; 10%) and grade 1–2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. ChiCTR2000034762.

Prostate cancer remains a significant public health problem, with limited therapeutic options in the setting of castrate-resistant metastatic disease. Angiogenesis inhibition is a relatively novel antineoplastic approach, which targets the reliance of tumor growth on the formation of new blood vessels. This strategy has been used successfully in other solid tumor types, with the FDA approval of anti-angiogenic agents in breast, lung, colon, brain, and kidney cancer. The application of anti-angiogenic therapy to prostate cancer is reviewed in this article, with attention to efficacy and toxicity results from several classes of anti-angiogenic agents. Ultimately, the fate of anti-angiogenic agents in prostate cancer rests on the eagerly anticipated results of several key phase III studies.

Immunotherapy has been a new standard for recurrent/metastatic head and neck cancers (R/M HNC). One of the prominent characteristics of cancer immunotherapy is the induction of immune memory followed by endured treatment response. However, whether and how a treatment delay would impact on the efficacy of immunotherapy has not been well determined. During the outbreak of COVID-19, a number of cancer patients in Wuhan, the epicenter of the pandemic in China, had experienced long-lasting city lockdown and delay of immunotherapies. Here, we retrospectively analyzed 24 HNC patients treated with immune checkpoint inhibitors in our cancer institute prior to the outbreak of COVID-19 who were re-evaluated after the restoration of regular medical care. Of these 24 patients, 10 patients had achieved complete response (CR) or partial response (PR), 12 patients had achieved stable disease (SD), and 2 patients had received just one cycle treatment without efficacy evaluation before treatment delay. The median delay was 3.75 months (range 1.73–8.17 months). Re-evaluation after treatment delay revealed that ten patients (10/10) who achieved CR or PR, two patients (2/2) who received just one cycle treatment without efficacy evaluation and seven patients (7/12) who achieved SD before outbreak of COVID-19 maintained tumor response after treatment delay. Among the rest five patients who had achieved SD, four patients were re-evaluated as progressive disease (PD) due to treatment delay and one patient died after treatment interruption without re-evaluation. Our results from a small cohort of R/M HNC patients showed that treatment delay of three to four months might have mild, if any, impact on the efficacy of immunotherapy for patients with controlled disease.

Several bispecific antibodies (bsAbs) targeting BCMA, GPRC5D, and FcRH5 are in clinical trials for heavily pretreated multiple myeloma (MM) patients. Teclistamab was approved for relapsed/refractory MM therapy in 2022, while elranatamab, linvoseltamab, F182112, talquetamab, and cevostamab are currently undergoing clinical trials. This study summarizes several latest reports on bsAbs for the treatment of MM from the ASCO 2023 Annual Meeting.