The anticancer immune response: indispensable for therapeutic success?

Zitvogel, Laurence; Apétoh, Lionel; Ghiringhelli, François; André, Fabrice; Tesnière, Antoine; Kroemer, Guido

doi:10.1172/jci35180

Cited by 523 publications

(426 citation statements)

References 116 publications

(112 reference statements)

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“…This results in a mutated TLR4 protein (Asp299Gly, Thr399Ile) that exhibits a reduced affinity for HMGB1 . Importantly, breast cancer patients bearing this loss-offunction allele of TLR4 exhibit an accelerated relapse after anthracyclin-based adjuvant chemotherapy compared with patients bearing the normal TRL4 allele , underscoring the importance of anti-cancer immunity for an optimal response to anthracyclines (Zitvogel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Immunogenic death of colon cancer cells treated with oxaliplatin

et al. 2009

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Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNAmediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

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Section: Introductionmentioning

confidence: 99%

Immunogenic death of colon cancer cells treated with oxaliplatin

et al. 2009

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“…These drugs are also reported to enhance or permit effi cient tumour cell killing in vitro at concentrations comparable with the maximally achieved therapeutic concentration in vivo in humans [26]. There is recent evidence indicating that some cytotoxic compounds and radiotherapy promote specifi c anticancer immune responses that contribute to the overall therapeutic effect [27,28]. This study investigated whether trifunctional antibodies are able to induce effi cient anti-tumour activity with immune effector cells obtained from patients with HNSCC before, during and after chemotherapy, and following radio-chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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Background Trifunctional antibodies, such as catumaxomab (anti-EpCAManti-CD3) and ertumaxomab (anti-HER-2/neuanti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. Methods The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fl uorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. Results Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti-tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fl uorouracil treatment. Conclusion This study shows for the fi rst time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for effi cient killing of tumour cells.

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“…Because much needs to be researched, we have to concentrate on testing in the clinic both what makes sense and what is available right now, without complicated negotiations to obtain access to proprietary experimental drugs. Combination with chemotherapy or local irradiation [99], for example, is attractive. Anti-CTLA-4 antibodies will hopefully be approved soon [100], and can then be systematically tested also in the context of DC vaccines, which will be very interesting given promising observations in previously vaccinated patients [101,102].…”

Section: Combination Therapiesmentioning

confidence: 99%

Dendritic cells in cancer immunotherapy

Schuler

2010

Eur J Immunol

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DC initiate and regulate T‐cell immunity and are thus the key to optimization of all types of vaccines. Insights into DC biology offer many opportunities to enhance immunogenicity. In this Viewpoint, I discuss some recent developments and findings that are of immediate relevance for the clinical development of cancer vaccines. In addition, I emphasize my personal view that we should explore the potential of adoptively transferred DC (i.e. DC vaccination) as cancer vaccines by performing two‐armed trials that address critical variables and by delivering antigens via mRNA‐transfected DC.

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The anticancer immune response: indispensable for therapeutic success?

Cited by 523 publications

References 116 publications

Immunogenic death of colon cancer cells treated with oxaliplatin

Immunogenic death of colon cancer cells treated with oxaliplatin

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

Dendritic cells in cancer immunotherapy

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