Harnessing the power of the immune system in cancer immunotherapy and cancer prevention

Lu, Yong; Wang, Xiaojing

doi:10.1002/mc.23211

Cited by 5 publications

(7 citation statements)

References 28 publications

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“…Over the last decade, ICBs have revolutionized systemic therapy for cancer after inducing durable responses in some malignancies. Unfortunately, these cases represent a minority (typically 20%–30%) for most tumor types ( 42 ). Using orthotopic ICC models, we show that GC chemotherapy converts ICCs from “immunologically cold” tumors into “hot” tumors by increasing effector CD8 + T-cell recruitment facilitated by induction of normalization of ICC vasculature.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti–PD-1 Therapy

Chen,

Amoozgar,

Liu

et al. 2024

Cancer Immunology Research

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Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the PD1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-CTLA-4 when combined with anti-PD1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient since CD8+ T cells from Cxcr3+/+ but not Cxcr3–/– mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 “priming” with chemotherapy followed by anti-PD1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

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Section: Discussionmentioning

confidence: 99%

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti–PD-1 Therapy

Chen,

Amoozgar,

Liu

et al. 2024

Cancer Immunology Research

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show abstract

“…Over the last decade, ICBs have revolutionized systemic therapy for cancer after inducing durable responses in some malignancies. Unfortunately, these cases represent a minority (typically 20-30%) for most tumor types ( 37 ). Using orthotopic ICC models, we show that GC chemotherapy converts ICCs from immunologically “cold” tumors into “hot” tumors by increasing effector CD8 + T-cell recruitment facilitated by induction of vascular normalization.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy

Jiang

Amoozgar

Liu

et al. 2023

Preprint

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Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, andin vivoT-cell depletion and CD8+T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+T-cells. Depletion of CD8+but not CD4+T-cells compromised efficacy. Conversely, CD8+T-cell transfer from Cxcr3-/-versus Cxcr3+/+mice into Rag1-/-immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 ″priming″) with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

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“…Cancer immunotherapy is a therapeutic modality where the immune response is enhanced to eradicate tumour cells with the goal of extending progression-free survival (PFS) and overall survival (OS) [5][6][7]. When harnessed appropriately, cellular immunotherapy is intrinsically superior to conventional drugs, as cells are dynamic living agents with a multitude of dynamic capacities such as signalling cascades, secretion of cytokines, formation of immunological memory, and persistence in the body for months, or even years [29][30][31]. In contrast, conventional pharmaceuticals, which generally target specifc molecules or pathways, are excreted on average within hours of administration [4].…”

Section: Harnessing T Cells In Cancer Immunotherapymentioning

confidence: 99%

“…Conventional therapies also lack the ability to diferentiate between tumour and nontumour cells and indiscriminately target rapidly growing cells (cancerous or otherwise) [4]. Cancer immunotherapy can specifcally recognise unique mutations and protein expression of tumour cells and optimise the immune response to overcome standard evasive defence mechanisms of treatment resistance [29,30]. Tis capacity can be attributed to antigen-directed cytotoxicity, the ability to provoke a signalling cascade resulting in clearance of tumour cells and the durability, longevity, and functionality of the response [29].…”

Section: Harnessing T Cells In Cancer Immunotherapymentioning

confidence: 99%

Chimeric Antigen Receptor-T (CAR-T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective

Murnane,

Gardiner,

Crehan

et al. 2024

Journal of Clinical Pharmacy and Therapeutics

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Background. Chimeric antigen receptor (CAR) T cell therapy, a “living drug” immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of “Qualified Person” (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist.

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Harnessing the power of the immune system in cancer immunotherapy and cancer prevention

Cited by 5 publications

References 28 publications

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti–PD-1 Therapy

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti–PD-1 Therapy

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy

Chimeric Antigen Receptor-T (CAR-T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective

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