Late-Onset Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy

Importance: The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development. Objectives: To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs. Design, Setting, and Participants: This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025. Exposure: Late-onset irAEs. Main Outcomes and Measures: The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs. Results: Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti–programmed death ligand 1 (PD-L1) and anti–programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti–PD-L1–based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti–cytotoxic T-lymphocyte–associated protein 4 (P  Conclusions and Relevance: The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.</p

First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting

This review summarizes phase I trial results of 11 drugs presented at the American Society of Clinical Oncology meeting held in Chicago IL from May 30 to June 3rd 2008: BMS-663513, CT-322, CVX-045, GDC-0449, GRN163L, LY2181308, PF-00562271, RAV12, RTA 402, XL765, and the survivin vaccine

MiR-223 Suppresses Cell Proliferation by Targeting IGF-1R

To study the roles of microRNA-223 (miR-223) in regulation of cell growth, we established a miR-223 over-expression model in HeLa cells infected with miR-223 by Lentivirus pLL3.7 system. We observed in this model that miR-223 significantly suppressed the proliferation, growth rate, colony formation of HeLa cells in vitro, and in vivo tumorigenicity or tumor formation in nude mice. To investigate the mechanisms involved, we scanned and examined the potential and putative target molecules of miR-223 by informatics, quantitative PCR and Western blot, and found that insulin-like growth factor-1 receptor (IGF-1R) was the functional target of miR-223 inhibition of cell proliferation. Targeting IGF-1R by miR-223 was not only seen in HeLa cells, but also in leukemia and hepatoma cells. The downstream pathway, Akt/mTOR/p70S6K, to which the signal was mediated by IGF-1R, was inhibited as well. The relative luciferase activity of the reporter containing wild-type 3′UTR(3′untranslated region) of IGF-1R was significantly suppressed, but the mutant not. Silence of IGF-1R expression by vector-based short hairpin RNA resulted in the similar inhibition with miR-223. Contrarily, rescued IGF-1R expression in the cells that over-expressed miR-223, reversed the inhibition caused by miR-223 via introducing IGF-1R cDNA that didn't contain the 3′UTR. Meanwhile, we also noted that miR-223 targeted Rasa1, but the downstream molecules mediated by Rasa1 was neither targeted nor regulated. Therefore we believed that IGF-1R was the functional target for miR-223 suppression of cell proliferation and its downstream PI3K/Akt/mTOR/p70S6K pathway suppressed by miR-223 was by targeting IGF-1R

Selective BRAFV600E Inhibitor PLX4720, Requires TRAIL Assistance to Overcome Oncogenic PIK3CA Resistance

Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAFV600E alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAFV600E mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK) suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKOBRAFV600E/PIK3CAH1047 cells. In contrast, for the same level of apoptosis in HT29BRAFV600E/PIK3CAP449T cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAFV600E. TRAIL dependence on the constitutive activation of BRAFV600E is emphasised through the overexpression of BRAFV600E in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CAMT as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAFV600E mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAFV600E inhibitors in combination with TRAIL in a BRAFV600E mutated background and provided insight for new anti-cancer strategies where the activated PI3KCA mutation oncogene should be suppressed

Small molecules and targeted therapies in distant metastatic disease

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

The proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34 + cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL + cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34-TRAIL + cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34-TRAIL + cells. In fact, CD34-TRAIL + cells combined with perifosine, but not CD34-TRAIL + cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34-TRAIL + cells failed to affect the growth of SU-DHL-4V tumors, but CD34-TRAIL + cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature