scholarly journals Novel Combination Strategies to Enhance Immune Checkpoint Inhibition in Cancer Immunotherapy: A Narrative Review

2020 ◽  
Vol 8 (3) ◽  
pp. 273-280
Author(s):  
Jonathan A. Hermel ◽  
Cassi M. Bruni ◽  
Darren S. Sigal
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Inkt Cells ◽  
Combination Strategies ◽  
Car T

Programmed cell death protein-1 (PD-1) is an immune checkpoint receptor that induces and maintains tolerance of T cells, invariant natural killer T (iNKT) cells, and natural killer (NK) cells, among other lymphocytes. Immune checkpoint inhibition by PD-1 blockade restores the lymphocytic immunostimulatory phenotype and has been successful in the treatment of various malignancies. However, while immune checkpoint blockade has been shown to provide robust antitumor treatment outcomes, its overall response rate remains low in a significant portion of cancer patients. An essential unmet need in cancer therapy is the development of novel pharmacologic strategies designed to lower rates of resistance associated with immune checkpoint blockade. Therefore, efforts that seek to enhance the efficacy of PD-1 inhibition possess profound immunotherapeutic potential. Here, three promising combination strategies that harness the antitumor effects of immune checkpoint inhibitors (ICIs) together with non-ICI antitumor therapeutic agents are reviewed. These agents include (1) ABX196, a potent inducer of iNKT cells, (2) chimeric antigen receptor (CAR)-T cell therapy, and (3) NK cell therapy. A comprehensive literature search was conducted using the PubMed and ClinicalTrials.gov databases for scientific articles and active trials, respectively, pertaining to immune checkpoint inhibition, iNKT cells, CAR-T cells, and NK cell immunotherapy. Preliminary clinical and preclinical data suggest that these combination treatment regimens greatly suppress tumor growth and may serve as innovative methods to enhance and optimize anticancer immunotherapy.

scholarly journals Combination Immunotherapy Strategies in Breast Cancer

2019 ◽  
Vol 11 (4) ◽  
pp. 228-240 ◽  
Author(s):  
Brie M. Chun ◽  
David B. Page ◽  
Heather L. McArthur
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Clinical Investigation ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Combination Immunotherapy ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Combination Strategies

Abstract Purpose of Review We summarize combination immunotherapy strategies for the treatment of breast cancer, with a focus on metastatic disease. First, a general overview of combination approaches is presented according to breast cancer subtype. Second, additional review of promising combination approaches is presented. Recent Findings Combination strategies utilizing chemotherapy or radiotherapy with immune checkpoint inhibition are being evaluated across multiple phase III trials. Dual immunotherapy strategies, such as dual immune checkpoint inhibition or combined co-stimulation/co-inhibition, have supportive preclinical evidence and are under early clinical investigation. Modulation of the immune microenvironment via cytokines and vaccination strategies, as well as locally focused treatments to enhance antigenic responses, are active areas of research. Summary Pre-clinical and translational research sheds new light on numerous ways the immune system may be modulated to fight against cancer. We describe current and emerging combination approaches which may improve patient outcomes in metastatic breast cancer.

scholarly journals Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition

2017 ◽  
Vol 6 (6) ◽  
pp. e1315495 ◽  
Author(s):  
Takuya Osada ◽  
Michael A. Morse ◽  
Amy Hobeika ◽  
Marcio A. Diniz ◽  
William R. Gwin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 7-7
Author(s):  
Paul G. Pavicic ◽  
Patricia A. Rayman ◽  
Hussein Al-Sudani ◽  
C. Marcela Diaz-Montero ◽  
Haider Mahdi
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Synergistic Effect ◽  
Immune Checkpoint ◽  
Low Dose ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Activated T Cells

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.

CXCR1/2 blockade to enhance response to immune checkpoint inhibition in an aggressive orthotopic pancreatic adenocarcinoma model.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 19-19
Author(s):  
Nicholas A. Ullman ◽  
Luis I. Ruffolo ◽  
Katherine M. Jackson ◽  
Alexander Chacon ◽  
Mary Georger ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Immune Checkpoint ◽  
Chemokine Receptors ◽  
Therapy Group ◽  
Neutrophil Migration ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

19 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR+ CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p = <0.05). There were no differences in chow consumption between the control and medicated chow groups. Conclusions: CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. [Table: see text]

Abstract 2568: CAR T cells secreting an immune checkpoint blockade scFv have enhanced anti-tumor efficacy

2018 ◽  
Author(s):  
Sarwish Rafiq ◽  
Oladapo Yeku ◽  
Hollie Jackson ◽  
Terence purdon ◽  
Dayenne van Leeuwen ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Car T Cells ◽  
Car T

scholarly journals Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Wang ◽  
Gurbakhash Kaur ◽  
Alexander I. Sankin ◽  
Fuxiang Chen ◽  
Fangxia Guan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Hematologic Malignancies ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals 287 Combined COX-2 inhibition with fish oil and aspirin as adjuncts to anti-PD-1 immunotherapy in metastatic melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A311-A311
Author(s):  
Alexander Chacon ◽  
Alexa Melucci ◽  
Shuyang Qin ◽  
Paul Burchard ◽  
Katherine Jackson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fish Oil ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Omega 3 ◽  
Melanoma Patients

BackgroundOnly 30–40% of metastatic melanoma patients experience objective responses to first line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI). Cyclooxygenase (COX-1/2) inhibition with aspirin (ASA) and other non-steroidal anti-inflammatory drugs has been associated with prolonged time to recurrence and improved responsiveness to ICI in human melanoma,1 with inhibition of myeloid-induced immunosuppression in the tumor microenvironment (TME) a purported mechanism.2 Similarly, dietary omega-3 fatty acids metabolized by COX-2 elicit downstream effects on T-cell differentiation akin to ASA administration, abrogating murine melanoma and human breast cancer progression. Mechanisms of ICI resistance remain unclear, and adjunct therapies look to bridge the gap from current response rates to cure.MethodsYUMM 1.7 melanoma cells were injected into flanks of C57-BL6/J mice. Mice were fed control diets or supplemented with omega-3 rich fish oil (FO) chow (10% weight/weight, 30%kcal/kcal), ASA in drinking water (ASA, LO – 300, MED – 600, HI - 1000 ug/mL), or the combination of these agents (COMBO, with ASA-MED) starting at day 7 post tumor implantation. Intraperitoneal αPD1 was administered every 3–4 days starting at day 12. Tumors were assessed for growth, harvested at day 32 (day 26 for ASA LO/HI), and characterized with flow cytometry. All significant results (p<0.05) assessed by 2-way ANOVA or t-test as appropriate.ResultsFO resulted in lesser tumor volume at day 32 in αPD-1 treated mice, while ASA-HI resulted in lesser tumor volume in mice not treated with αPD-1 but did not synergize with αPD-1. ASA-MED and COMBO groups trended towards decreased tumor size (p = 0.07 and 0.07 respectively) by day 32 in αPD-1 treated mice. FO and COMBO increased total CD3+ T-cells and monocytes (CD45+, CD19-, CD11b+, Ly6C+, Ly6G -) in the TME. FO increased PD-L1 + CD4+ T-cells, while COMBO increased total CD8+ T-cells and PD1+ CD8+ T-cells. ASA-HI increased monocytes and the proportion of PD-1+, CD8+ T-cells in the TME.ConclusionsMyeloid-induced suppression of T-cell function in tumors may contribute to immune checkpoint inhibition resistance. In the present study, both fish oil and aspirin altered melanoma tumor growth, with only fish oil synergizing with anti-PD-1 at the doses assessed. Both fish oil and aspirin augmented monocyte populations in the tumor microenvironment, with differential effects on T-cell populations. The partially synergistic mechanism between substrate-limited (FO) and pharmacologic (ASA) inhibition of cyclooxygenase-2 may provide a cost-effective avenue to combat immune escape in melanoma patients treated with anti-PD-1 immune checkpoint inhibition, requiring further investigation in humans.ReferencesWang SJ, et al. Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer. J Immunother Cancer 2020;8(2).Zelenay S, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70.

Sign in / Sign up

Export Citation Format

Share Document