Immunoincompetence in cancer patients. Assessment by in vitro stimulation tests and quantification of lymphocyte subpopulations.

The authors performed a variety of lymphocyte-stimulation tests and quantified several lymphocyte subpopulations in 73 healthy controls and 72 patients with advanced cancer who were no longer receiving anticancer therapy. As a group, cancer patients had fewer lymphocytes and helper cells, but a greater proportion of suppressor cells and Ia+ cells than controls. The ratio of helper to suppressor cells was lower in the cancer group. Uptake of 125I-uridine was markedly depressed in cancer patients in the face of stimulation with various plant lectins, foreign lymphocytes, and varicella-zoster antigen. There was little correlation between any of the stimulation tests and any of the lymphocyte subpopulation proportions or numbers. The two tests that were most frequently abnormally low among the cancer patients were percent lymphocytes and number of helper cells (81% each). The most frequently abnormal functional assay in patients was pokeweed mitogen stimulation (59%). Three separate statistical methods selected the combination of percent lymphocytes, percent Ia+ cells, percent suppressor cells, number of helper cells, and pokeweed mitogen stimulation as being the best predictors of cancer/immunoincompetent status. This study confirms the breadth of immunoincompetence in advanced cancer patients as defined by in vitro techniques. A smaller battery of tests can be useful in monitoring the immune status of such patients, especially during therapy with proposed immune modulators.

In vivo immune restoration in advanced cancer patients after administration of thymosin fraction 5 or thymosin alpha 1.

Since patients with advanced cancer are usually immunodeficient, they might benefit from therapy with thymic hormones, which have an immunorestorative effect in immunosuppressed laboratory animals. We treated 14 patients with thymosin fraction 5 (TF5), and 14 patients with thymosin alpha 1 (TA1) over the dose ranges of 60-960 mg/m2 and 0.6-9.6 mg/m2, respectively. In addition to monitoring toxicity, we studied patients extensively using a variety of lymphocyte cell surface markers and in vitro functional assays, both before and following treatment. Approximately one-half of the in vitro tests were abnormal in the cancer patients prior to treatment. Overall, 28.4 and 18.3% of abnormal tests were improved following TA1 and TF5, respectively. On the other hand, 16% of normal tests became abnormal after therapy. Most of these responses occurred within 24-48 h and seldom persisted beyond 72 h. An optimum dose of TF5 was not readily identified, but 1.2 mg/m2 of TA1 was associated with substantial improvement in 46% of abnormal tests. Twelve of 14 cancer patients who received TF5 and 13 of 14 who received TA1 showed significant improvement in at least one in vitro test. Tumor responses were not seen, but the study suggested thymosin treatments would need to be repeated every 2-3 days to sustain an immune response. TF5 and TA1 are well tolerated as single i.m. injections, and have immunorestorative potential in cancer patients. Additional studies with repeated thymosin doses in more homogeneous cancer populations appear to be justified.

Delayed hypersensitivity and acquired cellular resistance in guinea pigs infected with Listeria monocytogenes.

Randomly bred pigs of both sexes were injected intracardially with one-half of a 50% lethal dose of Listeria monocytogenes. When infected animals were skin tested with 30 mug of a water-soluble extract of sonically disrupted Listeria, both males and females had uniformly detectable levels of delayed hypersensitivity (DH) 4 days after infection. In males, cutaneous hypersensitivity to Listeria antigens reached a peak on day 5 or 6 of infection, and high levels of DH persisted through the 7th week. In females, DH reached a peak on day 6 or 7, remained at this level through the 4th week, and then dropped sharply. Cutaneous reactivity was usually higher for males than for females, and differences between the sexes were statistically significant 5, 6, and 7 weeks after infection. Low levels of DH were still present 41 weeks (females) or 46 weeks (males) after infection. Assays to determine the number of viable Listeria present in spleen homogenates indicated that bacterial multiplication occurred only during the first 24 hours of infection. The number of Listeria declined steadily thereafter, and by day 13 no bacteria could be recovered from the spleens of infected animals. Spleen assays indicated that Listeria-infected animals of both sexes were resistant to a small challenge dose of Listeria given 48 hours, 7 days, or 2 weeks after the primary infection. Resistance to re-infection was absent in females challenged at 41 weeks and in males challenged at 46 weeks.

Recall of acquired cellular resistance in mice by antigens from killed Brucella.

Mice infected with Brucella abortus 19 were challenged intravenously with Listeria monocytogenes. Spleen assays to determine the number of viable Listeria cells present revealed that these mice were highly resistant to Listeria when challenged on day 17 of the Brucella infection. Resistance was absent in mice challenged on the 5th day and was declining in mice challenged on the 33rd day. Resistance could not be detected by day 49 of the Brucella infection but could be recalled by the injection of antigens from smooth B. abortus 2308. Thus, extracted antigens appeared to be as effective in recall as the live cells used in earlier studies. Similar injections of extracts from rough B. abortus 45/20, or from B. ovis REO 198, were also effective in recalling resistance; this suggests that the smooth surface agglutinogen may be relatively unimportant in recall.