The predictive value of tumour-infiltrating lymphocytes for response to immunotherapy.

A. Håkansson M.D., Ph.D. a, B. Gustafsson M.D., Ph.D. b and L. Håkansson M.D., Ph.D.

a Department of Oncology, Divison of Clinical Tumour Immunology; bDepartment of Pathology and Cytology; University Hospital, SE-581 85 Linköping, Sweden.

Aim: Despite various treatment strategies metastatic malignant melanoma is still associated with a poor prognosis. Immunotherapy and biochemotherapy have shown promise with a subset of durable responses. However, for the majority of patients with metastatic disease the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Our group has shown the importance of CD4+ lymphocytes infiltrating melanoma metastases for being a responder to interferon-alpha, (A. Håkansson et al., Br J Ca, 74, 670-676, 1996) as well as to biochemotherapy (A. Håkansson et al., In press, Br J Ca). Moreover, there is also a need for tests monitoring the patients during treatment to understand better the mechanisms of action and whereby tumours escape immunosurveillance. Methods: In our studies pre-treatment fine needle aspirates (FNA) were obtained from patients with melanoma metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Patients were treated with interferon-alpha (IFN-alpha) as single drug (10 million IU SC three days a week) or with biochemotherapy (Cisplatinum 30mg/m2 d.1-3, DTIC 250mg/m2 d.1-3 iv and IFN-alpha 2b 10 million IU SC three days a week, q 28d). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in the pre-treatment FNA, and the presence of these lymphocytes was correlated to response. Therapeutic efficacy was also evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Results: Statistically significant correlations were found between moderate/high degrees of pre-treatment CD4+ lymphocytes and response to IFN-alpha as well as to biochemotherapy. In biochemotherapy pre-treatment CD4+ lymphocytes were also significantly correlated to a longer time to progression as well as to longer overall survival. During the second week of treatment, areas with histopathological regressive tumour changes appeared. After biochemotherapy, these areas where found in about 70% of the biopsies from patients with regional as well as systemic disease. A close correlation was shown between extensive histopathological tumour regressive changes after biochemotherapy and longer overall survival. Also extensive regressive changes were correlated to moderate/high degrees of pre-treatment CD4+ lymphocytes analysed in FNA. Conclusions: There seems to be a need for CD4+ lymphocytes infiltrating the tumours before start of IFN-alpha therapy as well as before biochemotherapy to make the treatment successful. Determination of these cells in fine needle aspirates seems to be a method to predict responders. As close correlations also were shown between high degrees of histopathological tumour regressive changes after biochemotherapy and survival, analysis of tumour biopsies after therapy seems to be of value. This technique also allows a detailed analysis of anti-tumor reactivity and escape mechanisms.

For more information, contact

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.