Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier

Vafaei, Somayeh; Zekiy, Angelina Olegovna; Khanamir, Ramadhan Ado; Zaman, Burhan Abdullah; Ghayourvahdat, Arman; Azimizonuzi, Hannaneh; Zamani, Majid

doi:10.1186/s12935-021-02407-8

Cited by 122 publications

(92 citation statements)

References 312 publications

(271 reference statements)

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“…Immune checkpoint inhibitors (ICIs), represented by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed cell death protein ligand 1 (PD-L1) inhibitors, have transformed cancer treatment since ipilimumab was first approved for melanoma in 2011 (1). ICIs bring lasting objective remission to patients with cancer by activating autologous lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

et al. 2022

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BackgroundNon–small cell lung cancer (NSCLC) has entered the era of immunotherapy. However, only partial patients were able to benefit from immune checkpoint inhibitors (ICIs). Currently, biomarkers for predicting patients’ response to ICIs are primarily tumor tissue dependent and have limited accuracy. There is an urgent need to explore peripheral blood-based biomarkers to predict the efficacy and safety of ICI therapy.MethodsTo explore the correlation between lymphocyte subsets and the efficacy and safety of ICIs, we retrospectively analyzed peripheral blood lymphocyte subsets and survival prognosis data of 136 patients with stage IV NSCLC treated with ICIs.ResultsThe two factors that had the greatest impact on the prognosis of patients with NSCLC treated with ICIs were CD4+CD45RA− T cell (HR = 0.644, P = 0.047) and CD8+ T/lymphocyte (%) (HR = 1.806, P = 0.015). CD4+CD45RA− T cell showed excellent predictive efficacy (AUC = 0.854) for ICIs monotherapy, with a sensitivity of 75.0% and specificity of 91.7% using CD4+CD45RA− T cell >311.3 × 106/L as the threshold. In contrast, CD8+ T/lymphocyte (%) was only associated with the prognosis but had no predictive role for ICI efficacy. CD4+ T cell and its subsets were significantly higher in patients with mild (grades 1–2) immune-related adverse events (irAEs) than those without irAEs. CD8+CD38+ T cell was associated with total irAEs and severe (grades 3–4) irAEs but was not suitable to be a predictive biomarker.ConclusionPeripheral blood CD4+CD45RA− T cell was associated with the prognosis of patients with NSCLC applying ICIs, whereas CD8+CD38+ T cell was associated with irAEs and severe irAEs.

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Section: Introductionmentioning

confidence: 99%

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

et al. 2022

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“…However, other studies have examined staggered dosing of these agents and many have demonstrated that timing of checkpoint inhibition is critical [60,61]. Other studies have also demonstrated that the benefits of immune checkpoint inhibition used in conjunction with chemotherapy occur at specific dose ranges [62,63]. Additionally, it is important to note that divergent tumor biology may contribute to conflicting Th1/Th2 cytokine profiles.…”

Section: Discussionmentioning

confidence: 99%

Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer

et al. 2022

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Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.

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“…Therefore, targeting several processes in cancer cells may increase the therapeutic e ciency of therapy. For this reason, combination therapy has been shown an effective antitumor response rather than monotherapy [32]. Currently, the reports of various research show that despite the robust results of chemoimmunotherapy in comparison with chemotherapy alone, it has not improved outcomes in patients [33].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of HIF-1α Inhibition, Toll-Like Receptor 7 Agonist, and Chemotherapy in Mice Model of Colon Cancer

Rostamizadeh

Ramazani

Monirinasab

et al. 2022

Preprint

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Recently, combination therapies have become a promising option with hopeful therapeutic outcomes due to their strong antitumor effects. Among them, despite the great success of cancer chemoimmunotherapy, it has not been able to improve the outcome of patients. Immunosuppressive tumor microenvironment (TME) has been recognized as the main barrier to immunotherapy. So, it has been assumed that targeting HIF-1α as a reshaping of TME combined with chemoimmunotherapy can capably enhance the antitumor response of therapy. Herein, we have studied the therapeutic effects of HIF-1α inhibition combined with chemoimmunotherapy. We established CT26 mouse models to assess the synergistic effect of genetic silencing of HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth and TME. We showed that in comparison with dual combination therapy, mice treated with triple combination therapy exhibited a significant delay in tumor growth, which was correlated with high levels of cellular immune-related cytokines. Besides, mice without HIF-1α siRNA treatment exhibited high tumor growth and high levels of immunosuppressive factors, indicating an immunosuppressive phenotype. Briefly, we found that HIF-1α inhibition could synergize with OXA and IMQ to inhibit tumor growth in vivo. Our data suggest that targeting HIF-1α represents a promising strategy to enhance the antitumor response of chemoimmunotherapy.

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Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier

Cited by 122 publications

References 312 publications

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer

Synergistic Effects of HIF-1α Inhibition, Toll-Like Receptor 7 Agonist, and Chemotherapy in Mice Model of Colon Cancer

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