Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy

Kenichiro Hasumi, Yukimasa Aoki, Ryuko Wantanabe, Dean L Mann, Kenichiro Hasumi, Yukimasa Aoki, Ryuko Wantanabe, Dean L Mann

Abstract

Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T-cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with ≤ 5 neoplastic lesions that were ≤ 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8+CD56+ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8+ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease.

Keywords: activated T cells; cancer vaccine; cytotoxic T lymphocytes; immature dendritic cells; intratumoral injection.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3858384/bin/onci-2-e26381-g1.jpg
Figure 1. Immunoradiotherapeutic protocol employed in this study. (A) DC-IMRT protocol: sequence of administration of immature dendritic cells (iDCs), activated T cells and intensity modulated radiation therapy (IMRT) followed by the re-administration of the iDCs and activated T cells. (B) CTL protocol: isolation of cells for the generation of cytotoxic T lymphocytes (CTLs) and timing of subsequent intratumoral injection (blue arrows).
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3858384/bin/onci-2-e26381-g2.jpg
Figure 2. Expression of CD3, CD8 and CD56 among peripheral blood mononuclear cells isolated before and after immunoradiotherapy. Representative dot plots of peripheral blood mononuclear cells (PBMCs) obtained from a patient with metastatic gastric cancer before (first panel in each row) and after (1st round, 2nd round, and 1-y follow-up, as indicated) the immunoradiotherapeutic regimen described in Figure 1A, upon staining with anti-CD3, anti-CD8 and anti-CD56 antibodies.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3858384/bin/onci-2-e26381-g3.jpg
Figure 3. Therapeutic responses to the intratumoral injection of therapy-primed cytotoxic T lymphocytes. Representative PET-CT images of metastatic lung cancer lesions (arrows) injected with autologous cytotoxic T lymphocytes (CTLs) generated ex vivo from CD8+ T cells isolated from the peripheral blood mononuclear cells upon the failure of immunoradiotherapy. The chronological progression is indicated by date and demonstrates tumor regression.

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