durable clinical benefit with nivolumab plus ipilimumab in dna mismatch repair 5

Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial

STRAEs were defined as AEs of special clinical interest meeting defined criteria that were grouped by specific category (e.g., endocrine, GI, hepatic, pulmonary, renal, and skin events) and had a potential immunologic etiology. IMAEs were defined as specific events that included diarrhea and colitis, hepatitis, pneumonitis, nephritis and renal dysfunction, rash, and endocrine events (adrenal insufficiency, hypophysitis, hypothyroidism/thyroiditis, hyperthyroidism, and diabetes mellitus). Safety was evaluated between the first dose and 30 days after the last dose of study therapy. IMAE analyses were conducted regardless of causality within 100 days of the last dose and limited to patients who received immune‐modulating medication (IMM), with the exception of endocrine events, which were included in the analysis regardless of treatment. IMMs, including corticosteroids and immunosuppressive agents, were used to manage sTRAEs and IMAEs per protocol‐specified algorithms 20. Time to onset of any grade sTRAEs or IMAEs was defined as the time between the day of the first dose of study treatment and the onset date of the earliest AE.

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer

Limitations to widespread use of neoadjuvant therapy have included inaccurate radiological staging, concerns about tumor progression while undergoing preoperative treatment rendering a patient incurable, and a lack of randomized data demonstrating benefit. However, there is great interest in neoadjuvant chemotherapy, and a number of trials are under way. Early follow up of the first phase III trial of neoadjuvant chemotherapy for colon cancer demonstrated tumor downstaging and suggested an improvement in disease-free survival with neoadjuvant chemotherapy, and it is hoped that this will translate into longerterm overall survival benefit. Clinicians should closely watch this developing field, consider the option of neoadjuvant chemotherapy for colon cancer patients, and actively seek out opportunities for their patients to participate in ongoing clinical trials to further inform this field in future. The 5-year survival probability for durable clinical benefit with nivolumab plus ipilimumab in dna mismatch repair patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease.

Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. To identify co-inhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor infiltrating T cells (TILs) from patients with GBM may reveal novel targets for immunotherapy. Focusing on PD-1 and TIGIT, we found that TIGIT and its ligand CD155 were highly expressed on GBM TILs but were near-absent in MS lesions, while lymphocytic expression of PD-1/PDL-1 was comparable. TIGIT was also up-regulated in peripheral lymphocytes in GBM, suggesting recirculation of TILs. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.

Table 2. Use of concomitant IMMs to manage sTRAEsa.

Additionally, we thank Michael Axelson, Danielle Greenawalt, David Leung, Demetrios Manekas, and Hao Tang for their support. Editorial assistance was provided by Christopher Reina of Chrysalis Medical Communications, Hamilton, NJ, and was funded by Bristol-Myers Squibb. The Senior Veterans Service Alliance is not a VA service organization and is not affiliated with the US Department of Veterans Affairs .Even though 90 days of active duty are required, only one of those days needed to be included in the dates listed below. Before work is started it must be approved and authorized by a HEAP Local District Contact.

It also highlights the latest research advances in immunotherapy for colorectal liver metastasis and identifies immunotherapy as a treatment regimen with a promising future in clinical applications. Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor.

Cancer at Nature Portfolio

Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. Methods Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab, were developed. The use of targeted drugs in clinical practice has significantly increased patients’ overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment.

Immunotherapy in Chemotherapy-Refractory Disease

• With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable.
• Colorectal cancer (CRC) is the fifth leading cause of cancer‐related death worldwide, and by 2030, its global incidence is expected to increase by 60% 1, 2.
• Limitations to widespread use of neoadjuvant therapy have included inaccurate radiological staging, concerns about tumor progression while undergoing preoperative treatment rendering a patient incurable, and a lack of randomized data demonstrating benefit.
• Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages.

It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model.

Immune checkpoint inhibitors (ICIs) are shown to be effective among patients with metastatic colorectal cancer (mCRC) harboring high microsatellite instability (MSI-H) and/or mismatch repair deficiency (dMMR), with U.S. In Europe, only pembrolizumab in the first line and the combination of nivolumab and ipilimumab beyond the first line are approved. The development of immune checkpoint inhibitors in the adjuvant and neoadjuvant settings is also of great interest for patients harboring MSI-H/dMMR… This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia.

• Immune checkpoint blockade is showing promising clinical activity in multiple tumors including colorectal and non-colorectal.
• Due to relatively favourable prognosis in comparison to the mismatch repair proficient (pMMR) CRC, the proportion of these tumours decreases to approximately 4-5% in patients with metastatic CRC (mCRC) (2).
• ORR and DCR were reported in 65 (55%) and 95 (80%) patients, respectively, and the combination had 32% grade 3–4 treatment-related adverse events 37.
• The primary objective of the study is to determine the overall response rate (ORR) for the NIVO+IPI regimen as assessed by blinded indepen…

The treatment paradigm of neoplastic diseases has dramatically shifted with the introduction of immune checkpoint inhibitors (ICI). They induce a durable response in a wide variety of solid tumors, but this response depends on the infiltration of lymphocytes capable of recognizing and killing tumor cells. The primary predictor of intrinsic immune resistance to ICIs is the absence of lymphocytes in the tumor, the so-called “cold tumors”. Colorectal cancer (CRC) remains one of the most common and challenging cancer, but it is not traditionally considered a highly immunogenic tumor.

In addition, because of the small sample size of patients with sTRAEs, it is not feasible to assess whether these sTRAEs were related to specific efficacy outcomes. Pooling sTRAE categories from patients with varying underlying biology may have contributed to the comparable efficacy observed in patients both with and without sTRAEs. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed.