Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms

Our plain-English summary of Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms, by Z.G. Fridlender, J. Sun, S. Singhal, et al (Molecular Therapy, 2010).

The study

• Authors: Z.G. Fridlender, J. Sun, S. Singhal, V. Kapoor, G. Cheng, E. Suzuki, S.M. Albelda
• Journal: Molecular Therapy
• Published: 2010;18(11):1947-59
• Cited by: 109 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy "primed" an initial strong antitumor immune response, subsequent "boosts" could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8(+) T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of "danger signals" and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy.

In plain English

This was a laboratory study in mice, not people. The authors tested whether chemotherapy (cisplatin plus gemcitabine, or gemcitabine alone in some models) given after virus-based immune gene therapy worked better than either treatment alone. Mice carried large tumors of mesothelioma (the AB12 cell line, which came from an asbestos-induced tumor in a mouse) or lung cancer. In the AB12 mesothelioma model, complete tumor regression occurred in 13 of 15 mice given the combination, compared with 5 of 15 given the gene therapy (Ad.IFNα) alone and 2 of 15 given chemotherapy alone. In one lung cancer model (TC1), all 5 combination-treated tumors went into complete remission. In genetically altered mice with lung cancer (eight mice per group), all combination-treated mice were alive at 120 days, when none in the other three groups were. The combination was linked with more tumor-targeting CD8 T-cells, and chemotherapy reduced several immune-suppressing cell types. The authors concluded the study showed the potential feasibility of using chemotherapy to boost this gene therapy. They noted that they focused on only one chemotherapy regimen, and that the mouse treatment schedule was compressed compared with human treatment.

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 models), with supporting cell-culture experiments
• Who was studied: Mice (Balb/C, C57BL/6, B6-129/J1 hybrids, and LSL KrasG12D mice) bearing large flank tumors of the AB12 mesothelioma cell line or the TC1, LLC or LKR lung cancer cell lines, or lung tumors in the Kras model. The main tumor experiments had 5 to 10 mice per group, and the Kras model had 8 mice per group.
• Exposure: Not an asbestos exposure study. The treatments studied were adenovirus-based immune gene therapy (Ad.IFNα, Ad.IFNβ, Ad.E7, or Ad.HSVtk with ganciclovir) followed by weekly cisplatin (3 mg/kg) and gemcitabine (120 mg/kg), or by gemcitabine alone in some models. The AB12 mesothelioma cell line used was derived from an asbestos-induced tumor in a Balb/C mouse.
• Main results:
  • AB12 mesothelioma tumors: complete tumor regression occurred in 13/15 mice given Ad.IFNα followed by chemotherapy, versus 5/15 given Ad.IFNα alone and 2/15 given chemotherapy alone.
  • TC1 lung cancer tumors: combination therapy induced complete remission in all 5 of 5 tumors.
  • Kras lung adenocarcinoma model (n = 8 per treatment group): all combination-treated mice were alive at 120 days, when no mice in the other three groups survived (P < 0.05).
  • Order of treatment: in Lewis lung carcinoma, only immunotherapy followed by chemotherapy caused significant tumor regression. In LKR tumors, the combined effect was similar in either order.
  • TC1/Ad.E7 model: immunotherapy followed by chemotherapy increased CD8+ T-cells inside tumors 20-fold over control (P < 0.05 versus each group).
  • Chemotherapy given after the vaccine reduced splenic T-regulatory cells by about 50% compared with vaccine alone (P < 0.05). Gemcitabine reduced splenic myeloid-derived suppressor cells in all groups.
  • Gemcitabine increased trafficking of labeled T-cells into TC1 tumors compared with control tumors (P < 0.001). It also activated NFκB in tumor cells (3.6-fold in cultured cells; 2.7-fold in tumors in mice).
• The authors' conclusion: The authors concluded that the study showed the potential feasibility of using chemotherapy to boost the immune effects of viral immunogene therapy, and suggested multiple mechanisms for this. They reported that the approach is being tested in a clinical trial in patients with mesothelioma.
• Limitations the authors state:
  • The authors focused on only one chemotherapy regimen (cisplatin and gemcitabine).
  • The mouse treatment schedule was compressed in time compared with human cancer treatment, because mouse tumors grow faster.
  • Too few mice were rechallenged in the chemotherapy-alone and vaccine-alone groups to properly evaluate long-term immune memory.
  • The separate contribution of each change in suppressor cells could not be determined.
  • Cross-priming was not directly measured.

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: Chemotherapy, Immunotherapy, Malignant Mesothelioma, Lung Cancer, Cisplatin, Gemcitabine, Tumor Microenvironment, Cytokine.

Related studies

• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
• Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model — E.S. Lambright, S.D. Force, et al. (2000)
• Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer — H.C. Hwang, W.R. Smythe, et al. (1995)
• Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy — W.R. Smythe, H.C. Hwang, et al. (1995)
• Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy — X.B. Deng, L. Xiao, et al. (2015)
• Chemotherapy and targeted therapies for unresectable malignant mesothelioma — R.J. Kelly, E. Sharon, et al. (2011)

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