Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors

Galluzzi, Lorenzo; Humeau, Juliette; Buqué, Aitziber; Zitvogel, Laurence; Kroemer, Guido

doi:10.1038/s41571-020-0413-z

Cited by 869 publications

(736 citation statements)

References 273 publications

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“…Also, the timing of immunotherapy may require reconsideration. Early application of ICI in the induction phase may improve efficacy by optimally exploiting the autologous immune response and immunostimulatory effects of chemotherapy [241,242]. This upfront setting will shortly be explored for Dinutuximab in HRneuroblastoma.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Wienke

Dierselhuis

Tytgat

et al. 2021

European Journal of Cancer

115

129

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Wienke

Dierselhuis

Tytgat

et al. 2021

European Journal of Cancer

115

129

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“…The immunoregulatory effects of low-dose chemotherapeutic drugs have been of particular interest within the field of oncology. [17][18][19][20][21][22] In genetically engineered lung adenocarcinoma mouse models, Pfirschke et al observed that low-dose oxaliplatin (OxP) combined with cyclophosphamide triggered immunogenic responses and provided benefits when combined with ICIs. 23 Similarly, Song et al demonstrated that low-dose OxP enhanced antitumor ectopic lymphoid-like structures (ELSs) in murine colorectal cancer models, and OxP combined with an anti-PD-L1 monoclonal antibody (mAb) significantly inhibited tumor growth.…”

Section: Open Accessmentioning

confidence: 99%

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Wang

et al. 2020

J Immunother Cancer

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BackgroundThe survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.MethodsCell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.ResultsLow-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.ConclusionsWe first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

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“…It has long been appreciated that some, but not all, chemotherapy can induce antitumor immune responses 60,61 . Chemotherapy may elicit antitumor immunity via three main mechanisms: the 'on‐target' or direct impact on tumor cells that induce their immunogenicity; the 'off‐target' effects on different immune cell subsets; and impact on whole‐body physiology that reshape antitumor immunosurveillance 62 . Like radiotherapy, chemotherapy‐induced DNA damage may also trigger the cGAS‐STING pathway to increase tumor immunogenicity 63 .…”

Section: Inducing Immunogenic Tumor Cell Death (Icd)mentioning

confidence: 99%

“…It is possible that this combination treatment is particularly effective at breaking peripheral immune tolerance; however, this remains to be proven. Despite this, combined chemotherapy and ICI has become the standard of care and is under continual refinement for patients with breast, non‐small‐cell lung cancer, colorectal, gastric, gastro‐oesophageal carcinoma or some lymphomas 62 …”

Section: Inducing Immunogenic Tumor Cell Death (Icd)mentioning

confidence: 99%

Therapeutic strategies to remodel immunologically cold tumors

Wang

Desai

et al. 2020

Clin & Trans Imm

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Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these ‘responsive’ tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near‐complete absence of lymphocytes from the tumor, so‐called immunologically cold tumors. Here, we propose two broad approaches to convert ‘cold’ tumors into ‘hot’ tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor‐beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen‐presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

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Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors

Cited by 869 publications

References 273 publications

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Therapeutic strategies to remodel immunologically cold tumors

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