Abstract P060: Identification of host-intrinsic resistance mechanisms to immune checkpoint inhibitors (ICI) in Diversity Outbred mice

2022 ◽  
Author(s):  
Justin Hackett ◽  
James Glassbrook ◽  
Maria Muniz ◽  
Heather M. Gibson
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Intrinsic Resistance ◽  
Diversity Outbred ◽  
Outbred Mice

scholarly journals Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms

2019 ◽  
Vol 121 (10) ◽  
pp. 809-818 ◽  
Author(s):  
Ibrahim Halil Sahin ◽  
Mehmet Akce ◽  
Olatunji Alese ◽  
Walid Shaib ◽  
Gregory B. Lesinski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Therapeutic Approaches ◽  
Intrinsic Resistance ◽  
Repair Deficiency ◽  
Infiltrating Lymphocytes

Abstract Metastatic colorectal cancer (CRC) with a mismatch repair-deficiency (MMR-D)/microsatellite instability-high (MSI-H) phenotype carries unique characteristics such as increased tumour mutational burden and tumour-infiltrating lymphocytes. Studies have shown a sustained clinical response to immune checkpoint inhibitors with dramatic clinical improvement in patients with MSI-H/MMR-D CRC. However, the observed response rates range between 30% and 50% suggesting the existence of intrinsic resistance mechanisms. Moreover, disease progression after an initial positive response to immune checkpoint inhibitor treatment points to acquired resistance mechanisms. In this review article, we discuss the clinical trials that established the efficacy of immune checkpoint inhibitors in patients with MSI-H/MMR-D CRC, consider biomarkers of the immune response and elaborate on potential mechanisms related to intrinsic and acquired resistance. We also provide a perspective on possible future therapeutic approaches that might improve clinical outcomes, particularly in patients with actionable resistance mechanisms.

scholarly journals Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Revati Sharma ◽  
Elif Kadife ◽  
Mark Myers ◽  
George Kannourakis ◽  
Prashanth Prithviraj ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Number Of Patients ◽  
Angiogenesis Pathway

AbstractVascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies.

scholarly journals Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Juan Chen ◽  
Aiqun Ren ◽  
Liang Zheng ◽  
En-Dian Zheng ◽  
Tao Jiang
Keyword(s):  
Combination Therapy ◽  
Liver Metastases ◽  
Predictive Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intrinsic Resistance ◽  
The Impact ◽  
Pan Cancer ◽  
Negative Predictive Factor

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P < 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P < 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

2022 ◽  
Author(s):  
Antonio Passaro ◽  
Julie Brahmer ◽  
Scott Antonia ◽  
Tony Mok ◽  
Solange Peters
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Primary Resistance ◽  
Previous Response ◽  
Immune Resistance ◽  
Clinical Resistance

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

scholarly journals The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors

2021 ◽  
Vol 15 ◽  
pp. 117955492199628
Author(s):  
Zhaozhen Wu ◽  
Pengfei Cui ◽  
Haitao Tao ◽  
Sujie Zhang ◽  
Junxun Ma ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Great Promise ◽  
Immunogenic Cell Death

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.

scholarly journals A Diversity Outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors

2021 ◽  
Author(s):  
JUSTIN B HACKETT ◽  
James E Glassbrook ◽  
Jennifer McCasland ◽  
Maria C Muniz ◽  
Nasrin Movahhedin ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Genetic Background ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Inbred Mice ◽  
Therapy Resistance ◽  
Genetic Linkage Analysis ◽  
Chromosome 13 ◽  
Diversity Outbred ◽  
Host Genetic

: Immune checkpoint inhibitors (ICI) have improved outcomes for a variety of malignancies; however, many patients fail to benefit. While tumor-intrinsic mechanisms are likely involved in therapy resistance, it is unclear to what extent host genetic background influences response. To investigate this, we utilized the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. DO mice are an outbred stock generated by crossbreeding 8 inbred founder strains, and CC mice are recombinant inbred mice generated from the same 8 founders. We generated 207 DOB6F1 mice representing 48 DO Dams and demonstrated that these mice reliably accept the C57BL/6 syngeneic B16F0 tumor and that host genetic background influences response to ICI. Genetic linkage analysis from 142 mice identified multiple regions including one within chromosome 13 that associated with therapeutic response. We utilized 6 CC strains bearing the positive (NZO) or negative (C57BL/6) driver genotype in this locus. We found that 2/3 of predicted responder CCB6F1 crosses show reproducible ICI response. The chromosome 13 locus contains the murine prolactin family, which is a known immunomodulating cytokine associated with various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Prolactin augmented ICI response against B16F0, with 5/8 mice exhibiting slowed tumor growth relative to controls. This study highlights the role of host genetics in ICI response and supports the use of F1 crosses in the DO and CC mouse populations as powerful cancer immunotherapy models.

scholarly journals Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 835
Author(s):  
Sonja Vukadin ◽  
Farah Khaznadar ◽  
Tomislav Kizivat ◽  
Aleksandar Vcev ◽  
Martina Smolic
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Significant Proportion ◽  
Resistance Mechanisms ◽  
Advanced Melanoma ◽  
Mutational Status ◽  
Primary Drug Resistance

Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.

scholarly journals Analysis of the immune landscape of small bowel neuroendocrine tumors

2019 ◽  
Vol 26 (1) ◽  
pp. 119-130 ◽  
Author(s):  
M Cives ◽  
J Strosberg ◽  
S Al Diffalha ◽  
D Coppola
Keyword(s):  
Small Bowel ◽  
Tumor Cells ◽  
Neuroendocrine Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Resistance Mechanisms ◽  
Immune Infiltration ◽  
Programmed Death

Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30–49%) and 14/102 (14%; 95% CI, 8–22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25–44%), mild to moderate in 46/102 samples (45%, 95% CI, 35–55%), intense in 21/102 tumors (21%, 95% CI, 13–30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11–26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.

Sign in / Sign up

Export Citation Format

Share Document