Intravenous Corynebacterium Parvum Research Articles

Phase III study on the treatment of women with cervical cancer, stage IIB, IIIB, and IVA (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radiotherapy plus immunotherapy with intravenous Corynebacterium parvum: A gynecologic oncology group study

A report on a study conducted under the auspices of the Gynecologic Oncology Group on the treatment of women with advanced carcinoma of the uterine cervix (stages IIB, IIIB, IVA) with radiotherapy alone versus radiotherapy plus immunotherapy (intravenous Corynebacterium parvum) is presented. There were 283 patients considered evaluable for analysis. Of these, 135 patients were randomized to radiotherapy plus C. parvum (120 patients received at least one course) and 148 were randomized to radiotherapy only. The two treatment regimens were similar for those adverse effects commonly associated with radiation therapy but for hematologic toxicity and fever and/or chills were significantly more frequent among those patients who received C. parvum. There was no statistical difference in the treatment regimens with regard to survival or progression-free interval. Of the 42 patients with positive periaortic nodes, 19% were alive at 3 years. No therapeutic value was demonstrated by combining C. parvum therapy with traditional radiation therapy in advanced cervical cancer. Because of the greater frequency of adverse effects in those patients receiving C. parvum, the further use of C. parvum at this dose and schedule does not appear to be indicated for treating cervical cancer patients.

Distribution of intrapleural and intravenous Corynebacterium parvum in humans; 99mTc-, and 131I-labeled bacteria.

The distribution of Corynebacterium parvum labeled with 131iodine or 99mtechnetium was studied in 17 patients with bronchogenic carcinoma. The labeled bacteria were given intravenously or intrapleurally and monitored by whole-body gamma tracking and samples of blood and urine. Even though the rate of physical decay is quite different for 131iodine and 99mtechnetium, the tracking time of labeled bacteria was limited to 24 h after injection for both radioactive isotopes. Technetium labeling was preferred because of greater imaging resolution and less radiation dose to the patient. Following intravenous administration, labeled C. parvum was found predominantly in the liver and spleen, and in a lesser amount in the lung. Radioactivity was confined to the pleural cavity after intrapleural injection. These results suggest the combined intravenous and intrapleural route of adjuvant immunosupportive agents such as C. parvum for operable lung cancer patients.

Enhanced Fc receptor expression by a sub-population of murine intra-tumour macrophages following intravenous Corynebacterium parvum therapy.

Intravenous injection of Corynebacterium parvum (C. parvum) 4 days after s.c. inoculation of 5 X 10(5) cells derived from the immunogenic fibrosarcoma FSA/R induced tumour growth inhibition over a period of 21 days in syngeneic C3H/Buf mice. This was not accompanied by a change in the proportions of host cells within the tumour, but the activation state of tumour-infiltrating macrophages was increased following C. parvum therapy. Two macrophage subpopulations were identified in FSA/R tumours after fractionation by unit gravity velocity sedimentation. After i.v. C. parvum therapy the tumour-infiltrating macrophage subpopulation which sedimented between 1 and 6 mm h-1 was consistently activated as determined by measurement of Fc receptor avidity. Other intra-tumour macrophages were generally unaffected by C. parvum treatment. We have previously shown that the host cell fraction sedimenting between 1 and 6 mm h-1 is enriched with monocytes and the data presented in this paper suggest that these cells may enter the tumour in a pre-activated state following intravenous C. parvum therapy.

Improved survival in severely burned animals using intravenous Corynebacterium parvum vaccine post injury

Improved survival in severely burned animals using intravenous Corynebacterium parvum vaccine post injury

Serological changes following a single intravenous Corynebacterium parvum injection in the rat

Changes in circulating levels of immunoglobulins (IgM and IgG), C3, acute-phase reactants, total protein, albumin, iron, and indicators of hepatic and renal function were monitored for up to 3 weeks after a single IV Corynebacterium parvum (C. parvum) injection. In addition to a marked increase in immunoglobulins, there was also evidence of complement activation and of tissue injury typified by a classic acute phase response in levels of α2-macroglobulin and fibrinogen.

Disseminated intravascular coagulation following intravenous Corynebacterium parvum injection in the rat

Corynebacterium parvum (C. parvum) was administered by a single IV injection (14 mg/kg) to rats, and platelet counts, plasma fibrinogen concentrations and thrombin clotting times were monitored for up to 7 weeks. During this time histological and ultrastructural studies were also conducted. Thrombocytopoenia, hypofibrinogenaemia, and prolongation of the thrombin clotting time rapidly followed C. parvum injection and were accompanied by the appearance of platelet clumps and fibrin within blood vessels in a variety of tissues. This initial episode of disseminated intravascular coagulation (DIC) subsided 12–24 h after injection, but a more prolonged second episode of DIC occurred 1–3 days after injection. The results suggest that caution should be observed when systemic immunotherapy with C. parvum is proposed.

Effect of intravenous corynebacterium parvum on peripheral-blood effector cells of cancer patients.

The i.v. administration of Corynebacterium parvum (CP) to patients who had recently undergone resection of colorectal tumours was found to have the following effects: 1. Polymorphonuclear leucocyte counts were raised 24 h after CP administration, while both lymphocyte and monocyte counts fell during this period. Polymorph and lymphocyte counts had returned to pre-infusion levels at one week, but monocyte counts were significantly increased at this time. 2. The lymphocyte mitotic response to PHA was reduced during the 24 h after CP infusion. 3 The spontaneous, antibody-induced, and PHA-induced lymphocyte-mediated cytotoxicity against a nucleated target cell fell significantly 3 h after CP infusion, but these functions recovered by 7 days. 4. A rise in serum lysozyme was found 3 and 24 h after CP administration. However, these increased levels were not maintained beyond 24 h.

Antitumor activity of Corynebacterium parvum administered into the pleural cavity of mice

We investigated the efficacy of intrapleurally (IPl) injected 0.25 mg Corynebacterium parvum (CP) against pulmonary tumor deposits of four syngeneic murine tumors, C3Hf/Bu or CBA fibrosarcoma (FSa) or mammary carcinoma (MCa), and compared its efficacy with that of intravenous (IV) CP. A mode of action of CP given by IPl administration was also studied. When given to mice prior to the IV inoculation of tumor cells, IPl and IV CP reduced the number of metastases of C3Hf/Bu-FSa and CBA-MCa equally well. Intrapleural injection of CP within a week after tumor cell inoculation was more effective against metastases in the lung than IV CP. A combination of IPl and IV administration of CP was more effective in the therapy of lung metastases of CBA-FSa and CBA-MCa than either single treatment alone. Intrapleural and IV injections of CP augmented concomitant immunity to artificially produced lung metastases of C3Hf/Bu-FSa. Intrapleural CP was less effective than IV CP in inducing complete regression of the SC growing C3Hf/Bu-FSa.

Toxicity manifestations following intravenous Corynebacterium parvum administration to patients with ovarian and cervical carcinoma

Manifestations of clinical toxicity were evaluated following 341 courses of intravenous Corynebacterium parvum adjuvant immunotherapy in patients with ovarian and cervical carcinoma. Most patients exhibited symptoms of minor toxicity, which decreased in intensity as subsequent courses of therapy were administered. Temperature elevations to 38.5° C. were the most objectively measured signs of toxicity but temperature elevations greater than 38.5° C. occurred following only 20.5 per cent of the infusions. Blood pressure alterations were not a serious problem and no serious central nervous system or renal toxicity was noted. The minor side effects should not preclude the use of C. parvum as an immunopotentiating agent if it is shown to be beneficial in the treatment of human malignant disease.

Lysozyme levels and macrophage content of tumor tissue in C3H mice bearing fibrosarcoma transplants treated by radiation and Corynebacterium parvum.

Abstract Serum levels of lysozyme (SL) were measured in C3H mice bearing early generation isotransplants of a methylcholanthrene induced fibrosarcoma (FSa) and of a spontaneous mammary carcinoma (MCa). SL increased with growth of FSa beyond 1000 mm 3 ; in MCa mice, SL was independent of tumor volume. SL could not predict control probability for the FSa after treatment by irradiation or intravenous Corynebacterium parvum . The macrophage content of FSa decreased as tumors reached massive size; few macrophages were found in FSa growing in immunosuppressed hosts and in MCa in normal hosts. The administration of C. parvum did not substantially increase the macrophage infiltration of either FSa or MCa. The concentration of lysozyme per unit tumor volume increased slightly with progressive growth of the FSa, was low in FSa in immunosuppressed hosts and increased slightly in FSa mice given C. parvum . Macrophage content and TL of 8 mm diameter FSa did not predict control probability after treatment with irradiation or C. parvum. Moderate differences in macrophage content of immunogenic FSa may reflect degrees of efficiency of host response, but such differences are insufficient to serve as prognostic indicators. Macrophage content of tumors and TL may be of value in identifying weakly immunogenic tumors or hosts which mount only a feeble response.

Intravenous Corynebacterium parvum: an adjunct to chemotherapy for resistant advanced ovarian cancer.

This is a prelimianry report of an effort to treat women with advanced (Stage III and IV) ovarian cancer who had progressive disease in spite of previous surgery, chemotherapy and/or radiation by a program of reductive surgery, intensive immune stimulation and combination chemotherapy. An initial laparotomy was done where possible to reduce tumor burden, and then all patients were given intravenous corynebacterium parvum (C.P.) in escalating doses over a 10- to 14-day period. Cyclic chemotherapy with Cytoxan, adriamycin and 5-fluorouracil (CAF) was started and repeated monthly. Maintenance subcutaneous C.P. was given weekly. All patients had frequent follow-up clinical and laboratory examination. Immune function was measured by skin tests and in vitro tests prior to treatment and periodically during therapy. Two-thirds of the patients had depressed DNCB and PHA stimulation responses prior to treatment, and almost all had severely depressed lymphocyte counts. Thirty-nine patients entered the program. Exploratory laparotomy was done in 16 patients and in eight, successful tumor reduction was accomplished. Eleven patients received intravenous C. Parvum and all expired before receiving chemotherapy. Four patients received C. Parvum and less than three cycles of CAF; all expired within 2 months. Twenty-four patients received C. Parvum and less than or equal to three cycles of CAF. Four patients had complete regression of measurable disease and were living free of disease 9-12 months after starting CAF. Eight patients had more than 50% regression for a minimum of 3 months, and five were living with disease (LWD) 5-11 months. Five patients had 25% to 50% regression and three were LWD 4-8 months. Seven patients had no regression and all expired within 4 months. Of eight patients who had successful reductive surgery prior to treatment, three were free of disease, median of 10 months, and five had partial responses and were living with disease, a median of 9 months. Although pre-treatment immune function was better in the patients who had a good response to CP and CAF (10 of 12 were DNCB+) vs that in patients with a poor response (4 of 12 were DNCB+) immune function was not significantly improved during therapy. The initial treatment results in this program are encouraging and suggest that this approach may be useful in patients with earlier disease.