Cytokine gene therapy or infusion as treatment for solid human cancer

Our plain-English summary of Cytokine gene therapy or infusion as treatment for solid human cancer, by B.W. Robinson, S.A. Mukherjee, A. Davidson, et al (Journal of Immunotherapy, 1998).

The study

• Authors: B.W. Robinson, S.A. Mukherjee, A. Davidson, S. Morey, A.W. Musk, I. Ramshaw, D. Smith, R. Lake, T. Haenel, M. Garlepp, J. Marley, C. Leong, I. Caminschi, B. Scott
• Journal: Journal of Immunotherapy
• Published: 1998;21(3):211-7
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In the induction of tissue-directed immune responses, cytokines tend to be released within the affected tissues. We used two strategies to expose tumor tissues to continuous high levels of cytokines: First, a vaccinia interleukin (IL)2 recombinant was injected directly intratumorally 3-weekly at 10(7) pfus/dose in six patients with the solid tumor malignant mesothelioma (MM). No virus excretion was detectable. At each cycle vaccinia-IL-2 mRNA (SQ [semi-quantitative] reverse transcription polymerase chain reaction) was maximal 24-72 h following injection reduced at 8 days and faded by 21 days. No tumor regression occurred. Second, based on the success of granulocyte macrophage colony-stimulating factor (GM-CSF) in gene transfer experiments, we conducted a study using continuous intratumoral GM-CSF infusion in eight patients with MM using a portable pump at doses of 10 micro/cg/24 h over 8 weeks. Systemic neutrophil agglutination and local catheter-related difficulties occurred. Two patients demonstrated tumor necrosis, one of whom had a marked progressive mononuclear cell infiltration of the tumor associated with a partial response (>50% reduction in tumor area). Murine studies using our MM model in CBA and BALB/C mice have demonstrated that B7-1 and allo-class I transfections induce strong tumor-specific cytotoxic T lymphocyte responses: GM-CSF, IL-12, and IL-2 induced mixed nonspecific plus specific responses, whereas B7-2 and class II transfections were not effective. We conclude that increased intratumoral cytokine concentrations can be generated using both gene transfer and cytokine infusion approaches; however, both have their limitations and, at this stage, have not produced dramatic antitumor effects in humans.

In plain English

This article reported two small early treatment trials for malignant mesothelioma in Perth, Australia. The authors linked the cancer's relative frequency in their state to widespread crocidolite (blue asbestos) exposure; no patient exposure data were reported. Twenty patients were enrolled. Six had tumors injected with a vaccinia virus carrying the interleukin-2 (IL-2) gene. Viral IL-2 messenger RNA in tumors was high 1 to 5 days after injection, declining by day 8. No tumor regression occurred. Apart from slight fevers and modest, transient rises in white cell count, no significant toxicity was noted, and no contacts showed evidence of catching the virus. In eight patients, the cytokine GM-CSF was infused continuously into tumors by catheter; catheter problems were frequent. Two had neutrophil (white blood cell) clumping; during these periods one had worsening breathlessness and superior vena caval obstruction, the other a transient cerebral ischemic attack. Progression was reported in eight patients and reduction in two, which exceeds the eight GM-CSF patients described. One reduction was dead tissue around the infusion site; the other was a partial response. The authors concluded that neither approach had yet produced dramatic antitumor effects in humans.

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: Early clinical treatment study with two approaches: a vaccinia virus carrying the IL-2 gene injected into tumors, and continuous infusion of recombinant GM-CSF into tumors through a catheter. Not a study of asbestos exposure.
• Who was studied: 20 patients with pathologist-confirmed malignant mesothelioma, under 75 years of age, at the University Department of Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia. The article's summary describes six in the vaccinia-IL-2 study and eight in the GM-CSF study. Dates are not given.
• Exposure: The article reports no information on the patients' own asbestos exposure. The authors chose mesothelioma partly because it is relatively common in their state from widespread crocidolite (blue asbestos) exposure. The treatments studied were vaccinia-IL-2 injected into the tumor every three weeks, and human GM-CSF (Molgramostin) infused into the tumor continuously for 8 weeks. The GM-CSF dose units are garbled in the scan.
• Main results:
  • Vaccinia-IL-2 group (six patients): live virus could be cultured from biopsy tissue only during the first two cycles, and only in unvaccinated patients.
  • Vaccinia-IL-2 group: vaccinia-IL-2 mRNA levels in tumor tissue, measured by semiquantitative PCR, were high between days 1 and 5 after injection and declined by day 8. Results for all patients were pooled.
  • Vaccinia-IL-2 group: no tumor regression occurred.
  • Vaccinia-IL-2 group: no toxicity of any significance apart from slight fevers. There were no blood or biochemical changes apart from modest, transient increases in total white cell count.
  • None of the patients' contacts, vaccinated or unvaccinated, showed clinical or blood-test evidence of virus transfer.
  • GM-CSF group: frequent local problems, including local infection, blocked or dislodged catheters, sterile pus at the insertion site and discomfort. Two patients had pain requiring narcotic pain relief.
  • GM-CSF group: the two patients with the highest white cell counts had neutrophil clumping (agglutination). During these periods one had worsening breathlessness and superior vena caval obstruction, and the other had a transient cerebral ischemic attack.
  • GM-CSF section: tumor progression during treatment occurred in eight patients. Together with the two patients with tumor reduction, this is more than the eight GM-CSF patients described in the article's summary, so the number of patients these outcomes refer to is unclear.
  • GM-CSF section: two patients showed tumor reduction. In one, this was a 4 x 5 cm area of dead tissue around the infusion site.
  • GM-CSF group: the other patient had an intense lymphocyte infiltrate within the tumor, associated with a partial response.
  • Mean survival for 'the group overall' was 11 months, which the authors described as similar to historical controls. This is reported in the GM-CSF section.
• The authors' conclusion: The authors concluded that higher cytokine levels inside tumors can be produced by both gene transfer and infusion. They added that both approaches have limitations and, at this stage, had not produced dramatic antitumor effects in humans.
• Limitations the authors state:
  • Measurement of IL-2 expression was imprecise. It was hard to be sure biopsies came from the injected spot, and the PCR test was only semiquantitative, so results were pooled across patients.
  • Dead tissue around the catheter is hard to interpret, because a similar result could come from injecting any toxic substance.
  • The authors could not determine whether the immune cell infiltrate in the responding patient reflected specific antitumor immunity.
  • The infusion approach is technically demanding, which the authors felt limits its widespread use.
  • There is a theoretical risk of the tumor growing along the catheter.

Topics

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

Medical terms in this study, explained in our Lexicon: Cytokine, Malignant Mesothelioma, Macrophage, Necrosis.

Related studies

• Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation — S. Mukherjee, T. Haenel, et al. (2000)
• Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution — C. Jackaman, D.J. Nelson (2010)
• Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma — L. Cordier Kellerman, L. Valeyrie, et al. (2003)
• Gene therapy approaches for inherited and acquired lung diseases — D.T. Curiel, J.M. Pilewski, et al. (1996)
• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
• Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy — W.R. Smythe, H.C. Hwang, et al. (1995)

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