The Prognostic Significance of Immune Changes in Patients with Renal Cancer and Melanoma Treated with Interferon-α_2b

Abstract

We evaluated the response rate and the immunorestorative properties of subcutaneously administered in-terferon-α_2b (IFN- α_2b ) in patients with advanced renal cell carcinoma (RCC) and melanoma (MEL) and correlated the immune status with clinical responses. Thirty-five patients with advanced RCC and 12 with MEL were treated with re-combinant IFN- α_2b The dose was increased progressively from 5 × 10⁶ IU the first week to 10 × 10⁶ IU the second week and thereafter 15 × 10⁶ IU subcutaneously. The response rate for RCC patients was as follows: (1) 6 patients achieved partial responses; (2) 9 patients had stable disease, and (3) 20 patients progressed. The response rate for patients with MEL was as follows: (1) 4 patients experienced partial response and (2) 8 patients progressed. In all patients blood was withdrawn prior to IFN treatment and then monthly. T lymphocytes after isolation from peripheral blood were tested for proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and allogeneic mixed lymphocyte reaction (allo-MLR), interleukin-2 production (IL-2prod), expression of IL-2 receptors (IL-2rec) during the allo-MLR, and interleukin-1 production (IL-lprod) by peripheral blood monocytes. Striking increases were demonstrated in all parameters 1 month after treatment with IFN- α_2b. Patients with RCC experiencing a partial response showed a mean increase of 50% in the auto-MLR, 95% in the allo-MLR, 62% IL-2prod, 88% IL-2rec and 76% in IL-lprod. Patients with MEL presenting with a partial response showed a mean increase of 70% in the auto-MLR, 91% in the allo-MLR, 97% IL-2prod, 78% IL-2rec and 118% in the IL-lprod. On the contrary, the nonresponders had a decrease in the examined parameters, and in some, deterioration of the already depressed immunologic functions was observed. Therefore, in nonresponders with RCC the auto-MLR was decreased -23%, the allo-MLR -32%, IL-2prod -28%, IL-2rec -25% and IL-lprod -22%. In nonresponders with MEL the auto-MLR was decreased -22%, the allo-MLR -33%, IL-2prod -29%, IL-2rec -25% and IL-lprod -28%. Administration of IFN- α_2b results in a marked potentiation of deficient cellular immune response in vitro in those patients with RCC and MEL who respond to the treatment. On the contrary, the nonresponders demonstrated a decrease in the examined parameters and in some, deterioration of the already depressed immunologic functions was observed. Administration of IFN- α_2b results in a marked potentiation of deficient cellular immune response in vitro in those patients with RCC or MEL who respond to the treatment. This may have prognostic significance, and certainly more patients are required to be studied for definite conclusions.

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

“…We have previously demonstrated that localisation of CD4 þ , CD8 þ and CD57 þ lymphocytes to sites of tumour is a requisite for the response to therapy (Donskov et al, 2002a), thus hypothesising that the antitumour activity of IFN-a in vivo is primarily cellular immune mediated. This hypothesis is in accordance with previous in vitro findings (Kosmidis et al, 1992;Tsavaris et al, 1996).…”

“…Whereas cellular immune effector mechanisms are considered to be the most important mediators of IL-2 antitumour activity (Rubin et al, 1989;Donskov et al, 2002a), IFN-a in addition (Kosmidis et al, 1992;Tsavaris et al, 1996;Donskov et al, 2002a) is considered to exert antiproliferative (Grander et al, 1997) and differentiationinducing effects on the tumour cells (Pfeffer et al, 1998). In vitro, a direct antiproliferative effect on renal tumour cells has been demonstrated for IFN-a (Nanus et al, 1990), whereas IL-2 has no direct impact on cancer cells (Rosenberg, 2001).…”

Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes

“…Moreover, an important aspect of the present study was that baseline pretreatment measurements of IL-2, IFN-g, and GM-CSF serum levels, as well as NK and LAK cell cytotoxicity were depressed in patients (either in the paclitaxel or docetaxel group) compared to healthy normal blood donors, indicating impaired immunity at the start of treatment, a finding that is consistent to those regarding other tumour types investigated by our group in the past, such as colon cancer, melanoma and renal -cell carcinoma. For instance, most patients with colon cancer had impaired immunological parameter values after surgery, before the start of treatment and these returned to normal or surpassed it after responding to immunotherapeutic manoeuvres (Tsavaris et al, 1996;Baxevanis et al, 1997). In contrast, IL-6 serum levels were increased in our breast cancer patients at baseline, compared to normal controls and raised further significantly after treatment with both taxanes, a finding that might point to a direct effect of taxanes on hepatocytes or enhancement of tumour-induced Th2-directed inflammatory reaction.…”

Cancer immunotherapy: potential involvement of mediators

“…Of 12 melanoma patients, four patients showed a partial response whereas eight patients progressed. 109 In the case of 35 patients with advanced renal cancer, an increase in immune response potential was observed. 109 The conclusion was that more studies are required to determine the therapeutic effectiveness of INFa 2b .…”