Immune Modulating Effects of Low Doses of Cyclophosphamide and Keyhole Limpet Hemocyanine on Peripheral Blood Immune Parameters in Patients with Metastatic Renal Cell Carcinoma

Abstract

Assessing the peripheral blood immune status, we had found evidence of immunosuppression in metastatic renal cell carcinoma. Since immunosuppression might interfere with the outcome of immunotherapy, it was submitted to further investigation. Immunosuppression can be mediated by T suppressor cells, which for their part are inhibited by low-dose cyclophosphamide (Cy). We tested whether the immunomodulating effects of the biological response modifier keyhole limpet hemocyanine (KLH) on cellular and humoral immune parameters would be intensified by low-dose Cy. 10 patients were given 300 mg/m² Cy i.v. 3 days before application of 1 mg KLH i.m. up to 8 times in 4-weekly intervals. Immune parameters were assayed twice pretherapeutically, and prior to and 1 day and 1 week after each KLH injection. In contrast to the results obtained with KLH-monoapplication, lymphocyte subsets – with the exception of T4 cell counts and the T4/T8 ratio – remained stable during the first 4 months of observation. There were increases in immunoglobulines and in the immunoactivation markers tumor necrosis factor, neopterin and Β₂-microglobulin. The tendencies found here differed from those found in a previous study on patients who were given KLH alone, and were similar to those found in patients with nonmetastatic disease who received KLH alone. However, the increases of the activation markers during KLH + Cy application were at best half as much as in patients with nonmetastatic disease. In conclusion, immunosuppression was influenced, but not counterbalanced by low-dose Cy. Most probably other mediators of immunosuppression than T suppressor cells, for example prostaglan-din E₂, must be considered as well. Treatment of immunosuppression, however, seems to be a promising concept for improving the clinical results of immunotherapy.

Influence of Immunotherapy (IL2 + LAK + Inhibition of Prostaglandin Synthesis) on Peripheral Blood Immune Parameters and in vitro Cytokine Production in Metastatic Renal Cell Carcinoma

“…The macrophage products TNF, IL 1 and PGE2, a potential immunosuppressive agent, were ele vated pretherapeutically. This result supports our hypoth esis that immunsuppression in metastatic renal cell carci noma is mediated at least in part by PGE2 [6,8]. The in vitro PGEt production could be reduced therapeutically by applying piroxicam, the other macrophage activation markers TNF and IL 1 were influenced in the same way.…”

“…immunomonitoring must be regarded as an essential component of immunotherapy which allows optimization of therapy schedules by giving insight into the patients' individual immune system and the effect of immunotherapy. By means of monitoring cellular and humoral immune pa rameters of the peripheral blood during unspecific immunostimulalion in patients with metastatic RCC, we had found evidence of immunosuppression, which may im pair the immunostimulating effects of immunotherapy [6][7][8][9]. Immunosuppression in tumor patients can be me diated through different pathways ( fig.…”

The Role of the CTLA4 Blockade in the Treatment of Malignant Melanoma

“…Cyclophosphamide is one such agent that has demonstrated such activity in both murine and human systems (for review, see Bass and Mastrangelo (61)). This drug's immune modulating activities have been demonstrated several times in patients with metastatic melanoma and renal carcinoma (62,63).…”

Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin

“…of the tongue and urethra [20]. Besides local infiltration of immunocompetent cells into the bladder wall and tumour tissue, followed by secretion of various lymphokines into the lumen of the bladder, there are indications of a systemic activation of the immune system [21]. Local inflammatory reactions in the patients in the present study differed between and within The intravesical instillation of KLH [7] in patients after complete transurethral tumour resection induces an infiltration of immunocompetent cells into the bladder wall.…”