The combination of checkpoint immunotherapy and targeted therapy in cancer

Karachaliou, Niki; Cao, María González; Sosa, Aaron E.; Berenguer, Jordi; Bracht, Jillian Wilhelmina Paulina; Ito, Masaoki; Rosell, Rafael

doi:10.21037/atm.2017.06.47

Cited by 57 publications

(49 citation statements)

References 57 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role and the profiling of the immune environment is gaining attention in oncology and in melanoma research because of the growing evidence of its impact on both prognosis and response to immunotherapy. 28,29 To our knowledge, studies on canine melanoma immunology are few, and the use of immunotherapy targeting immune checkpoint molecules is still limited to in vitro data. 1,5,35,67 This study was intended to provide a first overview on the expression of FoxP3 and IDO in primary melanocytic tumors of the dog; moreover, it investigates the possible value of these molecules as additional prognostic immunohistochemical markers in canine melanoma.…”

Section: Discussionmentioning

confidence: 99%

FoxP3 and IDO in Canine Melanocytic Tumors

et al. 2018

View full text Add to dashboard Cite

Human melanoma is one of the deadliest forms of cancer, with poor prognosis and high resistance to chemotherapy and radiotherapy. The discovery of immunosuppressive mechanisms in the human melanoma microenvironment led to the use of new prognostic markers and to the development of immunotherapies targeting immune checkpoint molecules. Immunoescape mechanisms in canine melanoma have not yet been investigated, and no such immunotherapy has been tested. The aim of this study was to provide preliminary data on the expression of transcription factor forkhead box protein P3 (FoxP3) and indoleamine 2,3-dioxygenase (IDO) in primary canine melanocytic tumors and to investigate their prognostic role. Formalin-fixed, paraffin-embedded samples from 74 canine melanocytic tumors (26 oral melanomas, 23 cutaneous melanomas, and 25 cutaneous melanocytomas) were retrospectively evaluated by immunohistochemistry to explore the expression of FoxP3 and IDO. An increased risk of death due to melanoma was associated with a higher number of FoxP3+ cells per high-power field (FoxP3+/HPF), a higher percentage of CD3+ cells that were also FoxP3+ infiltrating and surrounding the tumor (%FoxP3), and a higher number of IDO+ cells/HPF (IDO+/HPF). A prognostic value for FoxP3 and IDO is suggested by our study, with optimal cutoffs of 14.7 FoxP3+ cells/HPF, 6.1 IDO+ cells/HPF, and 12.5% FoxP3+ cells. Both markers were also associated with tumor type. Multivariable analysis identified IDO+/HPF ( P < .001) as an independent prognostic marker. Even though stratification by diagnosis caused a loss of significance, results from the present study suggest a prognostic role for IDO and FoxP3, possibly related to the establishment of an immunosuppressive microenvironment.

show abstract

Section: Discussionmentioning

confidence: 99%

FoxP3 and IDO in Canine Melanocytic Tumors

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Several trials with therapy combination are ongoing: NCT01738139 involves patients with different advanced solid malignancies, including GIST, treated with a combination of Imatinib and Ipilimumab (anti-CTLA-4). Similarly, other trials are evaluating the efficacy of the combined use of TT agents (vemurafenib, cobimetinib, sunitinib, erlotinib and others) with ICI (pembrolizumab, anti-PD1, atezolizumab, anti-PDL-1, ipilimumab) in melanoma, NSCLC and RCC [188,189,192]. Several clinical trials exploiting the use of anti_TIGIT/TIM-3 blocking mAbs are also on going, either as monotherapy or mainly in combination with other anti-PD-1 or anti-PDL-1 mAbs while no one in combination with TT agents [193].…”

Section: Resultsmentioning

confidence: 99%

Targeted Therapies: Friends or Foes for Patient’s NK Cell-Mediated Tumor Immune-Surveillance?

Damele

Ottonello

Mingari

et al. 2020

Cancers

View full text Add to dashboard Cite

In the last 20 years there has been a huge increase in the number of novel drugs for cancer treatment. Most of them exploit their ability to target specific oncogenic mutations in the tumors (targeted therapies–TT), while others target the immune-checkpoint inhibitor molecules (ICI) or the epigenetic DNA modifications. Among them, TT are the longest established drugs exploited against a wide spectrum of both solid and hematological tumors, often with reasonable costs and good efficacy as compared to other innovative therapies (i.e., ICI). Although they have greatly improved the treatment of cancer patients and their survival, patients often relapse or develop drug-resistance, leading to the impossibility to eradicate the disease. The outcome of TT has been often correlated with their ability to affect not only tumor cells, but also the repertoire of immune cells and their ability to interact with cancer cells. Thus, the possibility to create novel synergies among drugs an immunotherapy prompted scientists and physicians to deeply characterize the effects of TT on immune cells both by in-vitro and by ex-vivo analyses. In this context, NK cells may represent a key issue, since they have been shown to exert a potent anti-tumor activity, both against hematological malignancies and solid tumors. In the present review we will discuss most recent ex-vivo analyses that clarify the effect of TT treatment on patient’s NK cells comparing them with clinical outcome and previous in-vitro data.

show abstract

“…MEK inhibitors can induce melanocyte-inducing transcription factor (MITF) and melanocyte-derived antigen expression, and enhance T cell infiltration to tumors similar to BRAF inhibitors. MEK inhibitors were also shown to generate an antitumor immune response by hindering the interaction between tumor cells and M2-like macrophages, thus allowing the tumor-specific effector T-cells to be trafficked to tumors [14].…”

Section: Therapies Targeting the Mapk Pathwaymentioning

confidence: 99%

“…Melanoma patients carrying a BRAF mutation have been shown to exhibit some short-term benefits from targeted therapies, such as MAPK inhibitors. Conversely, immunotherapy (such as immune checkpoint blockades) has been shown to induce longer-term responses in approximately one-third of patients [14]. Recent studies suggested that short-term inhibition of both BRAF and MEK in combination with anti-PD-1/L1 antibodies could enhance tumor immune infiltration, and improve tumor control in a CD8 T cells-dependent manner.…”

Section: Combination Of Immunotherapy and Targeted Therapymentioning

confidence: 99%

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Shin

Kim

Lim

et al. 2020

IJMS

View full text Add to dashboard Cite

The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.

show abstract

The combination of checkpoint immunotherapy and targeted therapy in cancer

Cited by 57 publications

References 57 publications

FoxP3 and IDO in Canine Melanocytic Tumors

FoxP3 and IDO in Canine Melanocytic Tumors

Targeted Therapies: Friends or Foes for Patient’s NK Cell-Mediated Tumor Immune-Surveillance?

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Contact Info

Product

Resources

About