Lymphocytic infiltration in the cutaneous lymphoma microenvironment after injection of TG1042

Abstract

Background: Primary cutaneous lymphomas (CLs), characterized by an accumulation of clonal T or B lymphocytes preferentially localized in the skin, have been successfully treated with interferons (IFNs) which counterbalance the Th2-immunosuppressive state associated with this pathology. In a phase I/II clinical trial, we correlated the local immune infiltrate and the anti-tumor effects of repeated intralesional administrations of an adenovirus vector expressing human interferon-gamma (IFN-g) termed TG1042, in patients with advanced primary cutaneous T-cell lymphomas (CTCL) or multilesional cutaneous B-cell lymphomas (CBCL).

Methods: For each patient, variation in time of specific lymphocyte populations, defined by immunohistochemical stainings, was assessed in biopsies of injected lesions. For each patient, the change in local immune response was associated with the patient's objective response at the end of the study.

Results: Immunohistochemical analyses of biopsies indicate that infiltration of CD8+ T lymphocytes and of TIA-1+ cytotoxic T-cells in lesions injected with TG1042 correlates with clinical benefit.

Conclusions: These data suggest for the first time that a CD8+ cytotoxic infiltrate, induced by local expression of IFN-g correlates with a clinical response.

Trial registration: The phase I step (TG1042.01) does not have a registration number. The phase II step (TG1042.06) registration number was NCT00394693.

Figures

Figure 1

Immune infiltrates in a CTCL complete responder before and after TG1042 treatment. Patient #24 at baseline (left panels) and at last visit, 4 weeks after last TG1042 injection (right panels). Percentages on pictures correspond to the ratio of DAB-positive cells on total hematoxylin-stained nuclei in the whole infiltrating population, as determined by ImageJ software macro-commands. The proportion of CD3 and CD4 expressing cells decreased at the last timepoint; the number of CD8 and CD79 α expressing cells increased between baseline and last visit.

Figure 2

Immune infiltrates in a CTCL progressive disease before and after TG1042 injections. Patient #27 at baseline (left panels) and at C1D16 (right panels). Percentages on pictures correspond to the ratio of DAB-positive cells on total hematoxylin-stained nuclei in the whole infiltrating population, as determined by ImageJ software macro-commands. The frequency of CD3 expressing cells increased between baseline and C1D16; CD4, CD8 and TIA-1 were stable markers. (Insert) TIA-1 staining is associated with intracellular granules.

Figure 3

Immune infiltrates in a CBCL complete responder before and after TG1042 injections. Patient #33 at baseline (left panels) and at C1D16 (right panels). Percentages on pictures correspond to the ratio of DAB-positive cells on total hematoxylin-stained nuclei in the whole infiltrating population, as determined by ImageJ software macro-commands. CD79α, CD20 and TIA-1 are stable markers; the frequency of CD8 expressing cells increased between baseline and C1D16.

Figure 4

Immune infiltrates in a CBCL partial responder before and after TG1042 injections. Patient #35 at baseline (left panels) and at C1D16 (right panels). Percentages on pictures correspond to the ratio of DAB-positive cells on total hematoxylin-stained nuclei in the whole infiltrating population, as determined by ImageJ software macro-commands. The frequency of CD79α, CD20, CD8 or TIA-1 expressing cells decreased between baseline and C1D16.