Thomas Stewart

IMMUNOCHEMOTHERAPY OF LUNG CANCER

After surgical resection of their primary lung cancer, 33 patients were randomized into one of three groups. The first received high-dose methotrexate once per month with citrovorum rescue, for 3 months. The second group were immunized monthly with a homogenate of Freunds complete adjuvant and carefully characterized soluble antigen derived from allogeneic lung cancer cells of appropriate histology, for 3 months. The third group received a combination of methotrexate and immunization monthly, for 3 months. Each patient was monitored immunologically before, during, and after the treatment period, by use of delayed hypersensitivity reactions to recall and cancer antigens, in vitro lymphocyte response to mitogens, and mixed lymphocyte blocking factor activity. The group that received methotrexate showed little change in skin reactivity, a reduction of blocking factor activity, and significant rebound overshoot in in vitro lymphocyte performance. The immunized group showed a tendency to production of blocking factor activity, striking conversion and enhancement of skin reactivity, and little change in in vitro lymphocyte performance. The immunochemotherapy group showed dramatic increases in specific skin reactivity to cancer antigens, up to 2 years after treatment, in vitro lymphocyte rebound overshoot, and reduction of blocking factor activity production. Classic life table analysis of the probability of freedom from metastases in patients with stage-I cancer indicate that the disease-free interval in patients who received methotrexate is longer than in historic and concomitant controls but not as long as in those who received immunization. The best group appear to be those who received combination immunochemotherapy. We emphasize that the small numbers in this pilot study do not yet allow firm conclusions to be made.

IMMUNOLOGICAL DETECTION OF RENAL ALLOGRAFT REJECTION IN MAN: INCREASED DEOXYRIBONUCLEIC ACID SYNTHESIS BY PERIPHERAL LYMPHOID CELLS

SUMMARY Immunological surveillance of 10 human renal allograft recipients was undertaken through serial study of lymphoblastoid cells in their peripheral blood. These cells were identified by their spontaneous uptake of 3H-thymidine. Two methods were used. In the first, 108 lymphocytes were cultured in 3 ml of media and plasma. In the second, 0.05 ml of blood was cultured in 2 ml of culture fluid. Results obtained with both methods allowed for the recognition and prediction of impending allograft rejection crises and for judging the adequacy of immunosuppressive therapy for these crises. The micromethod correlated with the method using 106 cells (r=0.82, significant at 0.001 level). Monitoring of lymphocyte responsiveness to phytohemagglutinin was of no value in evaluating efficacy of immunosuppression.

The presence of delayed hypersensitivity reactions in patients toward cellular extracts of their malignant tumors. 3. The frequency, duration, and cross reactivity of this phenomenon in patients with breast cancer, and its correlation with survival

In a group of 56 patients, 12 have shown a delayed hypersensitivity reaction (D.H.R.) to cellular extracts of their tumor. Such patients have anaplastic tumors with regional node metastases, and they tend to have significant stromal infiltrate of their tumor by mononuclear cells. Repeat skin testing with auto‐logous extracts gave weaker reactions, up to 34 months after the first skin testing. Antigen stored at‐20C causes a positive D.H.R. after 5 years in other patients, and cross reactivity occurred in approximately 50% of those cases tested. Shortened survival is seen in the majority of those patients who have a D.H.R. to their own tumor. This is interpreted as being due to inadequacy of this restraint of growth by the cellular defense mechanism in the face of a virulent tumor. In three patients who had an intense round cell infiltrate and a D.H.R. to the tumor, survival of 5, 5, and 5½ years, respectively, is seen.

HLA Antigens in Bronchogenic Carcinoma

A decrease in the frequency of HLA-A2 was noticed in 37 bronchogenic carcinoma patients studied. HLA-B8 was found to be increased in the prolonged survivors of bronchogenic carcinoma.

Specific active lung cancer immunotherapy. Immune correlates of clinical responses and an update of immunotherapy trials evaluations.

The mechanisms of action of the specific active immunotherapy of solid tumors have not been defined. In an attempt to characterize some of these mechanisms, we report controlled studies of humoral immune responses and cell‐mediated immune (CMI) responses in lung cancer patients with Stage I and Stage II adenocarcinoma and squamous cell cancer receiving pure tumor‐associated antigen (TAA) specific active immunotherapy or combination immunochemotherapy. At 5 to 6 months postimmunotherapy, the humoral immune response measurements are predictive of response to therapy/survival in early lung cancer patients, permitting decisions as to whether to continue therapy. Patients with adenocarcinoma respond to combination chemoimmunotherapy by showing stronger or earlier responses to tests of immunity. Cell‐mediated immunity to TAA at 17 to 24 months was far greater in patients receiving immunotherapy or immunochemotherapy compared with control patients, and also correlated with early humoral immune response and with 5‐year survival. Here we report a further subset analysis of Stage I and Stage II lung cancer patients in a successful Phase III US specific active immunotherapy trial as substantiating the experience with Stage I patients in a successful Phase II Canadian trial. We analyze failures and suggest additional therapies, especially a chemoimmunotherapy trial indicated by our analyses of humorocellular immune variables reported here.

Specific Active Immunotherapy in Lung Cancer: The Induction of Long-Lasting Cellular Responses to Tumour-Associated Antigens

In this report we give details of skin tests with soluble tumour-associated antigens in patients entered into the phase II trial of stage I lung cancer patients in Ottawa. We show that in non-immunized patients a weak positive reaction to such antigens following surgery is a favourable sign. Strong reactions in the group which received immunochemotherapy are associated with fewer failures than in the group which received immunization alone which had weak to moderate reactions. Strong delayed hypersensitivity reactions can be induced that endure more than 5 years. If such reactions indicate resistance to tumour growth, as in animal systems, then prophylactic immunization of healthy adults who are at high risk of developing lung cancer would be expected to reduce the incidence of the disease.

Specific Active Immunochemotherapy in Lung Cancer: A Survival Study

A radomized clinical trial of chemotherapy, immunization and immunochemotherapy among 55 patients with stages I and II carcinoma of the lung is reported. The survival rate in the immunized groups was significantly better (P = 0.001) than that in the nonimmunized groups. The results are discussed in the light of the reactivity of the patients to the specific cancer antigen.

A comparison of lung cancer antigens.

Un antigene (antigene Roma) separate e individuato dal tumore polmonare umano, e stato confrontato con un antigene a membrana solubiIe identificato dal gruppo della George Washington University. (antigene GWU) e con antigeni da cellule polmonari normali. Entrambi gli antigeni hanno prodotto reazioni cutanee intradermiche positive in pazienti cancerosi nel sistema autologo e allogenico. Questi risultati Indlcano che due gruppi cooperativi possono aver identificato un antigene eomune, associate con iI tumore polmonare umano, Seno necessarie ulteriori ricerche per· provare se questi antigeni possono 0 no essere un antigene polmonare fetale 0 un antigene virus-indotto presente sulla superficie cellulare,

Two patients with non-regional metastases of adenocarcinoma of the lung 11 and 14 years following surgery

Abstract Two patients are described who developed non-regional metastases of adenocarcinoma of the lung at 11, and 14 years following resection of the primary tumor. In each case a careful search failed to reveal a second primary lung tumor. The metastases were discovered in brain and a supraclavicular lymph node. Such distant metastases arising more than 10 years after primary surgery is a very rare event in adenocarcinoma of the lung. These patients were part of a small group who had received adjuvant immunochemotherapy following curative surgery. They developed moderate to very strong delayed hypersensitivity reactions to soluble tumor antigens that persisted from 10 to more than 14 years. The clinical course of these patients share many features with the conditions needed for the induction, maintenance and abrogation of tumor dormancy in animal models.

Mixed Lymphocyte Reactivity of Patients with Solid Tumors

The mixed lymphocyte reactivity of 22 solid tumor patients was studied prior to chemotherapy using the one-way (mitomycin-inactivation) assay. In 21/22 one-way studies the response of control subject cells in control plasma against patient cells were superior to the responses of patient cells in patient plasma against control subject cells. When cultured in control subject plasma, seven patients gave a better response than when cultured in autologous plasma. In eleven one-way studies the responses of control subject lymphocytes to patient lymphocytes were depressed on culture in patient plasma when compared to results obtained when cultured in control subject plasma. The authors conclude that (1) solid tumor patients with advanced disease may have impaired mixed lymphocyte reactivity, and (2) in some instances this depressed lymphocyte function may be due to a plasma factor.