Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes

Abstract

SummaryThe therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-α) correlates with the occurrence of CD4 + lymphocytes identified by fine-needle aspirates from melanoma metastases (Håkansson et al, 1996). The present investigation studies a possible correlation between tumourinfiltrating CD4 + lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m 2 d.1-3, DTIC 250 mg/m 2 d.1-3 i.v. and IFN-α2b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumourinfiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4 + lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4 + lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-α therapy alone, there seems to be a need for CD4 + lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs. The aim of the present investigation was therefore to study whether the presence of tumour-infiltrating CD4 + lymphocytes identified by fine-needle aspirates of melanoma metastases before treatment is started also correlates with the response to biochemotherapy. MATERIALS AND METHODS Study populationThis report describes 41 patients with metastatic malignant melanoma, 26 males and 15 females. The median age was 61 years (range 36-77) and Karnofsky performance status was 70 or more. Recurrences were cytologically verified by fine-needle aspirates before start of treatment. Two groups of patients were st...

On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases

“…In other studies, we have demonstrated that treatment with IFNa or IFNa in combination with cisplatin and DTIC results in early (incomplete) regression of metastases (Håkansson et al, 1996(Håkansson et al, , 2001. These responses showed a strong correlation with the amount of tumourinfiltrating CD4+ lymphocytes present before treatment.…”

“…However, objective remission following IFNa-based treatment is still only 15% (Legha, 1997). These observations suggest that an initial effective antitumour immune response is initiated following treatment, but that shortly thereafter immunological resistance occurs (Håkansson et al, 1999(Håkansson et al, , 2001.…”

“…Pretreatment investigations were as described previously (Håkansson et al, 2001). Treatment consisted of 30 mg m À2 cisplatin (cis-diamine-dichloro-platinum) and 250 mg m À2 dacarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1 -3 i.v., and 10 7 IU IFN-a2b 3 days a week s.c.…”

Intratumoral TLR-4 Agonist Injection Is Critical for Modulation of Tumor Microenvironment and Tumor Rejection

“…The presence of tumor infiltrate has been associated with good [2] or poor [1] prognosis, nonetheless it is now understood that it is the nature and state of activation, rather than number of infiltrating cells that actually influences the outcome. When we evaluated B16F10 melanoma growth, tumor histology showed that the subcutaneously injected B16F10 cells formed a considerable tumor mass, presenting a clear borderline dividing between tumor and surrounding connective tissue containing abundant infiltrate by immune cells (Figure 1(a)), which was absent in the control thigh (sham treated) (Figure 1(b)).…”

“…Infiltration of immune effector cells occurs early in the course of tumor growth, and in some cases cell infiltration correlates with disease outcomes [1][2][3]. However, the immune system is not always able to circumvent tumor growth.…”