IL-12 reverses cytokine and immune abnormalities in Sezary syndrome.

Abstract

Cutaneous T cell lymphoma is a lymphoproliferative disorder typically characterized by skin invasion of clonally derived malignant CD4+ lymphocytes that phenotypically resemble mature Th cells. Sezary syndrome (SzS) represents an advanced form of cutaneous T cell lymphoma associated with generalized erythroderma and involvement of the peripheral blood by the malignant cell population. We have previously demonstrated aberrant cytokine production by PBMC in SzS characterized by increased IL-4 and deficient IL-2 and IFN-gamma production, as well as increased expression of mRNA for IL-4 and IL-5 within active skin lesions, suggesting that the clonal T cell population is derived from the Th 2 subset of helper T lymphocytes. These findings have been associated with a constellation of immune abnormalities that have been attributed to the cytokine abnormalities. Because IL-12 is a potent inducer of IFN-gamma production, and causes the activation of cytotoxic lymphocytes, we examined the production of IL-12 by PBMC from SzS patients and whether IL-12 could alter the unfavorable cytokine balance typical of SzS and thus lead to correction of immune defects. Despite normal numbers of peripheral blood monocytes and normal TNF-alpha production, mean Staphyloccus aureus and LPS-induced IL-12 p40 and p70 production by SzS PBMC was significantly decreased compared with PBMC from normal controls. Mean IFN-gamma production by patient PBMC in response to PHA alone was depressed, but increased to levels comparable with normal after addition of 1 ng/ml IL-12. Pretreatment of PBMC for 24 h with IL-12, IFN-alpha, or both together resulted in a decrease in PHA-stimulated IL-4 production from a base line of 1818 pg/ml to 1520, 1350, and 1058 pg/ml, respectively. Lastly, culture of patient PBMC with IL-12 for 24 h also resulted in significant increases in NK activity against K562 cells. These results indicate that PBMC from patients with SzS manifest a defect in IL-12 production and that the cytokine abnormalities associated with SzS can be favorably altered by IL-12.

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets

“…Even if there are dated findings of a reduced or suppressed IL-12 pathway in CTCL development, especially in SS patients [60,101,158], studies regarding the impairment of the IL-12/23 axis in psoriatic patients have shown no evidence of an increased risk of altered clinical history in developing CTCLs [159]. Still, IL12/23 therapies are recent, and more long-term data are needed to confirm these findings.…”

“…Regarding the potential role of IL-12 as a treatment, there are some studies regarding the potential of the use of recombinant IL-12 in CTCLs: this is due to IL-12 being strongly able to induce Th-1 differentiation and conversion and suppressing Th-2 cytokines, making it a possible mechanism to treat MF and SS [60,138].…”

Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy

“…different TCL types and stages may be better suited for treatment with a therapeutic antibody versus a CAR-T), we also developed an allogeneic NK-cell based ADCC platform. As is generally known, patients with T cell malignancies often show increased opportunistic infections due to compromises in normal T cell and NK numbers and/or function [42][43][44][45][46][47][48][49][50][51][52][53][54][55] . We reasoned that allogeneic T cells with their more efficient transduction efficiency (relative to NK cell transduction) are suitable for CAR engineering directly, while donor NK cells could utilize infused therapeutic antibody via their Fc receptors as an alternative and complimentary therapeutic strategy.…”

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

“…The immunosuppressive effects of malignant T cells can be reversed with skin-directed and systemic therapies (10)(11)(12). However, it is unclear whether this is mediated solely by depletion of malignant T cells or if therapies that independently augment the immune system toward a type 1 helper T cell (T h 1) bias have greater efficacy.…”