Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity

Our plain-English summary of Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity, by W.J. Lesterhuis, J. Salmons, A.K. Nowak, et al (PloS One, 2013).

The study

• Authors: W.J. Lesterhuis, J. Salmons, A.K. Nowak, E.N. Rozali, A. Khong, I.M. Dick, J.A. Harken, B.W. Robinson, R.A. Lake
• Journal: PloS One
• Published: 2013;8(4):e61895
• Cited by: 123 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.

In plain English

This mouse experiment tested cancer treatments; it did not study asbestos exposure. Mice carried tumors from AB1-HA, an asbestos-induced mouse mesothelioma cell line, or from a Lewis lung cancer line. They received the chemotherapy drug gemcitabine, an antibody blocking CTLA-4 (a molecule that restrains T cells), or both. In the mesothelioma model, complete tumor regression was reported in 60% of mice given both, versus 13% with the antibody alone and 8% with gemcitabine alone (a symbol before each figure was garbled in scanning). The effect was less pronounced in the lung cancer model, and the antibody with cisplatin showed no clear synergy. Removing CD4+ or CD8+ T cells abolished the benefit. Of 14 mice cured by the combination, 13 resisted new mesothelioma cells lacking the added influenza gene; the authors took this as immunity not solely against that gene's antigen. The synergy appeared only when both drugs were given together. The authors concluded that anti-CTLA-4 and chemotherapy can act synergistically, and that each drug group's optimal schedule and immunogenicity should first be determined in pre-clinical models and small clinical studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mouse tumor treatment study)
• Who was studied: Laboratory mice aged 8 to 12 weeks at The University of Western Australia. BALB/C mice carried tumors from the asbestos-induced mouse mesothelioma cell line AB1, transfected with an influenza gene (AB1-HA). C57BL/6 mice carried Lewis Lung Cancer (LLC) tumors. For example, the main gemcitabine experiment pooled 87 mice from 5 separate experiments.
• Exposure: Treatments, not asbestos exposure: gemcitabine chemotherapy, an anti-CTLA-4 blocking antibody (clone 9H10), or both. Cisplatin chemotherapy was used as a comparison drug. The tumor cell line itself was asbestos-induced.
• Main results:
  • In the AB1-HA mesothelioma model, the share of mice with complete tumor regression was printed as 60% for the combination, 13% for anti-CTLA-4 alone and 8% for gemcitabine alone. A garbled symbol precedes each figure.
  • In the LLC lung cancer model, the combination also gave enhanced tumor control, but the effect was less pronounced.
  • When anti-CTLA-4 was combined with cisplatin instead of gemcitabine, there was no clear synergistic effect in either tumor model.
  • Mice given the combination showed a significant increase in activated CD4+ICOS+ T cells in the blood.
  • The benefit of the combination was completely abrogated when CD4+ or CD8+ T cells were depleted. Depleting NK cells (tested in the LLC model) did not affect it.
  • Of mice whose tumors completely regressed after combination treatment, 13 of 14 (93%) resisted a later injection of AB1 mesothelioma cells.
  • The rechallenge cells were AB1 cells without the influenza HA gene. The authors took this to indicate immunity against shared tumor antigens, not solely against the transfected HA antigen.
  • The synergy was seen only when the two drugs were given at the same time, not when one was given before the other. One mouse in the anti-CTLA-4-first group was culled for weight loss greater than 15%.
• The authors' conclusion: The authors concluded that anti-CTLA-4 therapy and cytotoxic chemotherapy can have a clear synergistic effect in treating cancer. They suggested that, for different groups of cytotoxic drugs, the optimal schedule and immunogenicity should first be carefully determined in pre-clinical models and small clinical studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Synergistic Effect, CTLA-4, Chemotherapy, Gemcitabine, Lung Cancer, Ovarian Cancer, Mesothelioma, Clinical Trial.

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