T. Mekori

Treatment of lung cancer by radiotherapy, chemotherapy, and methanol extraction residue of BCG (MER): clinical and immunological studies.

Fifty‐one patients with advanced lung cancer were divided at random into two groups. One group of 29 patients received the methanol extraction residue (MER) of Bacille‐Calmette‐Guerin (BCG) in addition to radiotherapy and/or chemotherapy. The other group of 22 patients was treated by radiotherapy and/or chemotherapy alone. The immune status of the patients was evaluated by skin tests to three recall antigens and KLH and by in vitro lymphocyte stimulation to PHA and three recall antigens. The immune status of both groups was similar before and after conventional treatment. The cutaneous reactivity, as well as the in vitro lymphocyte reactivity, became stronger in the MER‐treated group, as compared with the control group. The MER‐treated patients had less distant metastases. In a comparable clinical stage the survival in the MER treated group was slightly but not significantly better. This study has shown that MER stimulates the immune response, can be well tolerated, and has few side effects. Therefore, MER treatment of patients with minimal tumor load can ethically be done with hope of obtaining better results.

T-cell Subpopulation in Patients with Metastatic Renal Cell Carcinoma Treated by Recombinant Interleukin-2, Recombinant Interferon-α, 5-Fluorouracil, and Vinblastine

T-cell subpopulations were evaluated in 10 patients with metastatic renal cell carcinoma treated with recombinant interleukin-2, recombinant interferon-alpha, 5-fluorouracil, and vinblastine. T-cell subpopulation was tested by flow cytometry, and the results were compared with healthy control subjects. Mean T-cell values before treatment as compared with control were as follows: CD3, 68 vs. 73%; CD4, 34 vs. 53%; CD8, 38 vs. 31%; CD4/CD8, 1.1 vs. 1.8; CD4CD69, 20 vs. 47%, and CD8CD69, 24 vs. 19%. The difference in CD4, CD4/CD8, and CD4CD69 was statistically significant. After treatment (8 weeks), the values of CD4/CD8 ratio and CD4CD69 increased. Three patients achieved complete response, two partial response, and two had stabilization of the disease. After treatment, the CD4/CD8 ratio increased in complete responders, from 1.1 to 2.0, and CD4CD69 increased in complete and partial responders, from 11 to 37% and 23 to 31%, respectively. In nonresponders, no similar change was observed. In conclusion, increases in CD4/CD8 ratio and CD4CD69 levels in metastatic renal cell carcinoma patients may be associated with response to immunochemotherapy.

Multiple Lymphocyte Transformation Tests by Phytohemagglutinin in Healthy Individuals

146 serial determinations of spontaneous and phytohemagglutinin-induced lymphocyte transformation as measured by tritiated thymidine incorporation, were performed in 24 healthy individuals. 9 persons were studied intensively during a mean period of 40 days and the other 15 underwent random investigations during a period up to 10 months. Transient episodes of significant decreased lymphocyte transformation were revealed in 14 persons (58.4%) with regard to the spontaneous blastogenesis and in 11 subjects (45.8%) with regard to PHA-induced reactivity. The occurrence of the decreased values in PHA responsiveness was significantly higher in the intensively studied group compared to the randomly investigated one (p = 0.001). The probability of detecting one low PHA-related response in a normal subject was 11%. In only half of the cultures with low spontaneous blastogenic response did a simultaneous decrease in PHA-induced lymphocyte transformation occur. In addition to the currently used stimulation index, a new index termed the Blastogenic Cumulative Index is proposed. It is defined as the sum of the logarithms of the dpm values of the spontaneous and the PHA induced lymphocyte transformation. The CI is suggested to describe lymphocyte blastogenic function more accurately, and due to its simplicity warrents further study. Other indices for lymphocyte blastogenesis determination are discussed.

Leucocyte migration inhibition in Behçet's disease.

The leucocyte migration inhibition (LIF) was investigated in 16 patients with Behçets disease, 5 while in the active stage of the process, 3 both during relapse and remission, and 8 during remission of symptoms. In all patients skin tests with various antigens and with a needle prick and physiological saline were simultaneously performed. The results indicate a strong correlation between the activity of the disease, skin reactivity and the reactivity of LIF.

Cellular Immunity in Patients with Laryngeal Cancer Developing Additional Primary Malignant Tumors

Eleven patients with laryngeal cancer associated with additional primary tumors underwent cutaneous delayed hypersensitivity tests and lymphocyte stimulation studies with phytohemagglutinin for evaluation of their cellular immunity. Five of the 11 patients were anergic or hypoergic as shown by skin tests to recall antigens and seven of nine patients had impaired lymphocyte transformation. Depressed immunity was more often observed in patients with an active malignancy. The level of serum immunoglobulins was elevated in two of eight studied patients, and in the remaining patients was within the normal range. All patients had a history of excessive smoking. Most frequently, second tumors were found in the lung, urinary tract and skin. The prognosis seemed to be determined by the additional tumor rather than by the laryngeal cancer.

Immune Investigations and Therapy in Patients with Advanced Lung Cancer

SummaryFifty-one patients with advanced lung cancer were divided at random into two groups before conventional therapy was started. One group of 29 patients was treated with a Methanol Extraction Residue of Bacillus Calmette-Guérin (MER) administered intradermally in addition to the conventional radiotherapy and/or chemotherapy treatment. These patients will be referred to as the group. The other group of 22 patients was treated by the conventional method only and is designated the RC group.The general immunological status of these two groups of patients was evaluated once a month by the following in vivo and in vitro tests: Skin tests to five memory antigens: PPD, SK/SD, Candidin, Trichophytin, and mixed bacteria; lymphocyte stimulation in response to the mitogen PHA and to PPD and Candidin. In addition, E- and EAC-rosettes were determined in peripheral blood.The results show that after some of the treatments increased formation of E rosettes, improved in skin reactivity, and higher stimulation indices of cultured lymphocytes were found in the RCM group than in the RC group.

Lymphocyte Transformation in Competent and in Immunodepressed Individuals

Lymphocytes from 107 healthy individuals and 34 patients with lung cancer were cultured and stimulated with PHA. Wide variation in lymphocyte transformation reactivity was observed, ranging from significantly low responses to high blastogenesis. Low spontaneous blastogenic responses were not always associated with a simultaneous decrease in PHA-induced lymphocyte transformation in the same individuals. The results are presented by the (disintegrations per minute) values of the stimulated and nonstimulated cultures and by the stimulation index. A new index termed the Blastogenic Cumulative Index is proposed. It is defined as the sum of the logarithms of the values of the spontaneous and the PHA-induced lymphocyte transformation. A better relationship was observed in immunocompetent and in immunodepressed individuals between the dpm values and Cumulative Indices than between the dpm and the Stimulation Indices.

Oral administration of the methanol extraction residue of BCG (MER/BCG): A phase I study in non-oat cell lung cancer patients

Intradermal, interlesional and intravenous MER/BCG have been reported to possess immunostimulatory properties and combined with chemo-radiotherapy an anti-neoplastic effect. Due to local and systemic side effects of the methanol extraction residue of BCG therapy a new approach to oral administration was investigated. Seventeen patients with inoperable non-oat cell lung cancer were given oral MER for 30 days. Skin tests to 5 recall antigens and various concentrations of MER, lymphocyte stimulation by PHA were done before and repeated during therapy. The initial group of patients received a dose of 1.25 mg per day and when no side effects were detected the dose was gradually escalated in subsequent groups of patients up to 5 mg. Oral MER was well tolerated even at the higher dose with no clinical or laboratory side effects. No regression in tumor size was seen. In 6 of 17 patients the disease remained stationary for a mean of 6 months (Range 6-14 months). In the remainder, disease progressed after a mean of 15 weeks. Two patients had cutaneous PPD reactivity converted from negative to positive, in one it became negative, while the remaining patients maintained their original responsiveness. No major changes could be observed in the in vivo immune tests performed following the course of treatment. In view of the reported relative efficacy of oral BCG administration, and considering the very low toxicity with oral MER, further studies employing considerably higher doses of this nonviable vaccine are now justified.

Lymphocyte stimulation in patients with lymphoma cutis.

Lymphocytes from seven patients with lymphoma cutis were cultured and stimulated by phytohemagglutinin. The lymphocytes of six patients behaved like those lymphocytes from normal donors. The lymphocytes of the seventh patient were anergic.