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PubMedDate not supplied

Combination of adoptive immunotherapy with Herceptin for patients with HER2-expressing breast cancer.

Clinical use of Herceptin (trastuzumab), which is a humanized monoclonal antibody against HER2, started for patients with HER2-overexpressing breast cancer. To potentiate the efficacy of the Herceptin therapy, this study focused on the combination of Herceptin with activated immune lymphocytes. We used peripheral blood mononuclear cells (PBMCs) as effector cells and used HER2-unexpressing K562 cells, HER2-weakly-expressing breast carcinoma cells (Breast-M), or HER2-strongly-expressing breast carcinoma cells (BT-474) as target cells. Interleukin-2 (IL-2)-activated PBMCs, IL-2/OKT-3-activated PBMCs and a streptococcal preparation OK-432-activated PBMCs were generated and used as effector cells. Cytotoxic activity was determined with 4-hour 51Cr release assay. Both fresh PBMCs and activated PBMCs exhibited Herceptin-dependent cytotoxicity. Importantly, Herceptin-dependent cytotoxicity was found even at a lower effector to target cell ratio (E/T ratio) than that of Herceptin-independent cytotoxicity. In addition, Herceptin-dependent cytotoxicity by these activated PBMCs was observed even in HER2-weakly-expressing Breast-M cells. Since gamma-globulin or anti-CD16 antibody abrogated Herceptin-dependent cytotoxicity, it seems likely that antibody-dependent cellular cytotoxicity (ADCC) plays an important role in the Herceptin-dependent cytotoxicity. We present a recurrent breast cancer patient with malignant pleural effusion, in which HER2-strongly-expressing tumor cells were present, who was undergoing Herceptin therapy. Cluster formation between tumor cells and intrapleural mononuclear cells was induced 24 hours after intravenous injection of Herceptin (4 mg/kg). Mononuclear cells bound specifically to HER2-strongly-expressing tumor cells but not to other cells, such as mesothelial cells, suggested a Herceptin-mediated binding like ADCC in vivo. Taken together, these findings suggest that the combination of Herceptin with various types of activated lymphocytes may be a new therapeutic strategy, not only for HER2-strongly-expressing breast cancer but also for HER2-weakly-expressing cancer.

Adenocarcinoma↗
PubMed2001

Cancer treatment by photodynamic therapy combined with adoptive immunotherapy using genetically altered natural killer cell line.

Adoptive immunotherapy mediated by human natural killer (NK) cell line genetically altered to produce interleukin-2 (NK92MI) was evaluated as adjuvant to photodynamic therapy (PDT) of subcutaneous tumors. The combined effect of these two modalities was first examined with SiHa tumors (human cervical squamous cell carcinoma) growing in NOD-scid mice. The most effective protocol for NK92MI cell transfer in conjunction with PDT mediated by photosensitizer mTHPC was the injection of 5 x 10(7) cells (peritumoral or intravenous) given immediately after PDT, which produced a marked improvement in the therapeutic outcome compared with the effect of PDT alone. The same protocol was tested with HT-29 tumor model (human colorectal adenocarcinoma) xenografted in NOD-scid mice. The results demonstrate that the adoptive immunotherapy with NK92MI cells (which when used alone were not effective in controlling tumor growth) significantly improved the cures of PDT-treated HT-29 tumors, whereas such benefit was not observed with the parental cell line NK92 (not producing interleukin-2). Flow cytometry-based analysis revealed a higher percentage of p.t. injected NK92MI cells in PDT-treated than in non-treated HT-29 tumors. Further investigation showed that the NK92MI cell-based adoptive immunotherapy is also a highly effective adjuvant for PDT treatment of murine EMT6 tumors growing in immunocompetent syngeneic BALB/c mice. This result diminishes the concern that adoptively transferred NK92MI cells may be rendered ineffective by an allogenic reaction of the host. The findings of this study suggest that advanced protocols of NK cell-based adoptive immunotherapy can be developed as efficient adjuvants to PDT used for the treatment of solid malignant tumors.

Animals↗
PubMedDate not supplied

[The clinico-immunological validation of the combined use of specific immunotherapy and radon baths in pollinosis patients].

An original combination of specific immunotherapy and radon baths designed and tried by the author can produce a 7-7.5-fold decrease in the course duration. Local and systemic reactions occur less frequently while the response rises 1.5-2-fold. The effect was achieved by means of immunological mechanisms of phagocytic activation and rising titers of blocking antibodies.

Adolescent↗
PubMed1991

Elliptinium, norcantharidin and tetrachlordecaoxide in combined chemo-immunotherapy prolong the survival of Friend-virus-infected mice.

The association of several drugs with different target specificities has long been proven to be more efficient than one single agent in the treatment of cancer. This strategy might also be of benefit in the cure of retrovirus-induced diseases. The effectiveness of several drug combinations was evaluated on DBA/2 mice injected with Friend leukaemia virus (FLV). Elliptinium (ELP), a known chemotherapeutic agent with possible antiviral activity, was given in association with norcantharidin (NCTD) (shown previously to increase the cytotoxic potential of human lymphocytes) and/or in association with tetrachlordecaoxide (TCDO), which augments both humoral and cellular immune responses. ELP alone at a dose of 0.2 mg/kg in long-term treatment significantly increased the survival of mice infected by FLV. When ELP, TCDO (2 micrograms/kg) and NCTD (2 mg/kg) were given together, the survival time was prolonged 1.6 times and 2 times as compared to the group treated by ELP alone or to non-treated controls, respectively. Moreover, the combined treatment gave more effective inhibition of hepatomegaly than ELP alone, suggesting that this protocol might have an organ-specific effect and might suppress the leukaemogenesis induced by FLV in some erythropoietic organs. These results indicate that a chemotherapeutic agent (ELP) associated with two immunomodulatory substances (NCTD and TCDO) is more effective than chemotherapy alone in controlling retroviral infection and in the prolongation of survival. These data taken together suggest that the role of the two immunomodulatory agents might be to suppress the retroviral infection synergistically with ELP and enhance immune functions. Possible modes of action are discussed and are under investigation.

Adjuvants, Immunologic↗
PubMed1993

Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma.

Interleukin-2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 x 10(5) IU ip tid) on days 3-7; plus WBHT (41 degrees C for 30 min) on days 3, 5, and 7; or WBHT only days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10-14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature.

Animals↗
PubMed1995

Combination chemo-immunotherapy of murine solid tumor with OK-432, G-CSF, IL-2, and chemotherapeutics.

An experimental tumor model was previously established in which BALB/c mice could survive the otherwise fatal intraperitoneal (i.p.) inoculation of BAMC-1 fibrosarcoma cells if the mice were treated with five sequential i.p. injections of OK-432 (a potent BRM) starting 2 days after tumor inoculation. In the present study, although a single i.p. injection of OK-432 alone on day 2 was not enough to cure the tumor-bearing mice, a combination therapy, an injection of OK-432 (5 mg/kg) on day 2 followed by injection of G-CSF (50 micrograms/kg) on day 3, could eradicate the tumor cells in more than 80% of the mice. In contrast to this ascites tumor model, solid tumors induced by intradermal transplantation of BAMC-1 tumor cells were resistant to the combined treatments with OK-432 and G-CSF, dying within 60 days. However, when these mice received a combined chemoimmunotherapy with cisplatin, OK-432, G-CSF and IL-2, starting on day 4, the tumors had regressed, and were completely eradicated. When the same treatment was started as late as day 8, no significant therapeutic effect was observed. Even at this advanced stage, however, it was found that a similar chemo-immunotherapy protocol using CAP-D (cyclophosphamide, epirubicin and DWA2114R) in lieu of cisplatin was extremely effective, achieving the eradication of tumors in more than 70% of the mice. These results indicated that the combination therapy with OK-432, G-CSF, IL-2, and chemotherapeutics could achieve a potent anti-tumor effect against the solid tumor, even at the advanced stage. Subsequent experiments using athymic nude mice transplanted with the tumor cells revealed that the same combination therapy showed weak tumor-regressing effects without achieving a complete cure. These results suggest that T-cells are key effectors in this type of chemo-immunotherapy of malignant tumors.

Animals↗
PubMedDate not supplied

Effects of single and combined maltose tetrapalmitate immunotherapy, cyclophosphamide chemotherapy and radiotherapy on ethyl carbamate accelerated primary lung cancer in A/J mice.

A/J mice were given ethyl carbamate to accelerate and to raise to 100 percent the incidence of lung tumours at 34 weeks (day 237) of age. The animals were then divided into groups which received the following treatments: group 1, no treatment; group 2, MTP alone; group 3, radiotherapy alone; group 4, cyclophosphamide alone; group 5, radiotherapy + MTP; group 6, MTP + cyclophosphamide; group 7, radiotherapy followed by cyclophosphamide and group 8, MTP and radiotherapy together followed by MTP and cyclophosphamide. Except for radiotherapy, which was given for 5 consecutive days, MTP and cyclophosphamide were continued till the death of the animals. The treatment efficacies were evaluated by the number and size of tumour nodules, taking into consideration the survival time of the animal. Animals in groups receiving cyclophosphamide died earlier (between days 290 and 315) due to its toxic effects, and half of the radiotherapy-MTP were sacrificed at day 314 for comparison. Although cyclophosphamide alone and radiotherapy plus cyclophosphamide demonstrated antitumour activity, the number of tumour nodules and the nodule diameter were reduced most effectively in group 8 (receiving MTP, radiotherapy and cyclophosphamide). Among the animals in the non-cyclophosphamide group, radiotherapy alone was ineffective. MTP given before and after radiotherapy (group 5) kept tumour volume in control although this group died suddenly. The animals receiving only MTP died between day 430 and 470. The number of tumour nodules and the nodule diameter in the MTP group were, however, significantly reduced when compared to controls or radiotherapy group animals dying at or near the same time.

Animals↗
PubMed1990

AZT demonstrates anti-HIV-1 activity in persistently infected cell lines: implications for combination chemotherapy and immunotherapy.

A sensitive and quantitative focal immunoassay has been used to measure the effects of three different therapeutic agents on tissue culture cells infected with human immunodeficiency virus (HIV). The effects of the drugs were studied on both acutely and persistently infected CD4+ cell lines. The three agents, azidothymidine (AZT), interferon-alpha (IFN-alpha), and an anti-HIV envelope antibody coupled to ricin A chain, were tested alone and in combination. AZT was found to have its greatest effect during early stages of the infection, but also had an action on persistently infected T cell lines. The effect of AZT on persistently infected cells was seen within 24 h, increased with extended exposure to the drug, and persisted after its removal. IFN-alpha had variable effects on acutely infected cells but suppressed chronic infection. Combinations of the therapeutic agents were studied. Using a model that allowed for treatment during both acute and persistent stages of infection, the most effective combination in suppressing HIV infection was the continual use of both AZT and IFN-alpha at the highest tolerable doses. Knowledge of the efficacy of AZT on persistently infected cells will allow for the most effective design of clinical protocols.

Cell Line↗
PubMed2004

10-12 years follow-up of highly bacillated BL/LL leprosy patients on combined chemotherapy and immunotherapy.

This study reports the follow-up results of 36 highly bacillated untreated BL/LL cases who were serially allocated to three treatment groups. Group I patients received a modified WHO regimen (Rifampicin 600 mg once a month supervised, 50 mg of Clofazimine and 100 mg of Dapsone daily unsupervised) and BCG 0.1 mg per dose 6 monthly; group II patients received the same multi-drug treatment (MDT) and Mw (2 x 10(8) killed bacilli per dose) 6 monthly: group III patients received the same MDT with 0.1 ml of distilled water 6 monthly and acted as a control. Treatment was continued till smear negativity. All these three groups were comparable by their initial clinical score, bacteriological index (BI), viable bacilli as assessed by the mouse foot pad (MFP), bacillary adenosine triphosphate (ATP) content and also histologically at the time of starting treatment. All these parameters were evaluated every 6 months. The vaccines were well tolerated. All the patients in group I became smear negative by 3.5 years, in group II in 3 years whereas those in group III took 5 years. The incidence of reactions was the same in all the groups during the first 2 years, however, patients of group III (MDT + placebo) continued to have reactions up to 3 years. No viable bacilli could be detected in the local and distal sites as estimated by MFP and bacillary ATP after 12 months in both the immunotherapy groups. These could be detected in patients on MDT alone up to 24 months of therapy. Histologically patients in both the immunotherapy groups (groups I and II) showed accelerated granuloma clearance, histological upgrading and non-specific healing without granuloma formation both at the local and distal sites and this was achieved much earlier compared to the MDT + placebo group. Thus, by the addition of immunotherapy the effective treatment period of achieving bacteriological negativity could be reduced by about 40%, time period of reactions reduced by 33% and there were no reactions and/or relapses in the 10-12 years post-treatment follow-up.

Adenosine Triphosphate↗
PubMed1987

Combination tumor-immunotherapy with recombinant tumor necrosis factor and recombinant interleukin 2 in mice.

Recombinant human tumor necrosis factor (r-TNF) inhibits growth of various mouse tumor cell lines both in vitro and in vivo. Treatment of established tumor nodules with intratumoral (i.t.) injection of r-TNF caused hemorrhagic necrosis of tumor and temporary disappearance of tumor mass. However, a small number of tumor cells remained and later formed fresh nodules. In striking contrast, combination therapy with r-TNF and recombinant human interleukin-2 (r-IL-2) resulted in a marked inhibition of regrowth of tumor cells. More than 60% of MBL-2-bearing mice were completely cured of tumor by treatment with r-TNF and r-IL-2. Cured mice could also reject rechallenged MBL-2 lymphoma cells, indicating the generation of anti-tumor effector cells in vivo. However, lymphocytes obtained from mice cured of MBL-2 showed no significant in vitro cytotoxic activity against MBL-2 lymphoma cells. In contrast, in vitro sensitization of spleen cells from cured mice with mitomycin-C-treated MBL-2 lymphoma cells resulted in the generation of cytotoxic cells against MBL-2 lymphoma cells. Moreover, spleen cells from mice cured of MBL-2 by treatment with r-TNF and r-IL-2 revealed a strong anti-tumor activity upon in vivo neutralization tests. These results strongly suggest that tumor-bearing mice can acquire systemic immunological memory after combination therapy with r-TNF and r-IL-2.

Animals↗
PubMed2003

Gene therapeutic approaches for medullary thyroid carcinoma treatment.

Medullary thyroid carcinoma (MTC), a neoplasm of thyroid C-cells, is characterized by dominant activating mutations in the RET proto-oncogene. Currently therapy is restricted to surgical removal of all neoplastic tissue lacking alternative forms of treatment such as chemotherapy or radiotherapy. Therefore MTC is a particularly attractive target for gene therapeutic approaches. Many promising gene therapy strategies have been used in various animal models of MTC, showing enhanced antitumoral efficacy, and these will hopefully extend our current standard of care in the future. These approaches can tentatively be subdivided into four groups: (a) Inhibition of oncogenic RET signaling, (b) suicide gene therapy, (c) immunotherapy, and (d) combination of immunotherapy and suicide approaches. To block oncogenic signal transduction dominant-negative RET mutants were delivered into tumor cells and found to possess strong antineoplastic activity, including tumor growth suppression and increased animal survival. Suicide gene therapeutic approaches applied to MTC treatment featured either gene transfer of herpes simplex virus thymidine kinase with concomitant application of ganciclovir or delivery of nitric oxide synthase II. Here antitumor effects were attributed to the occurrence of substantial bystander activities. Immunotherapy approaches comprised stimulation of immune response by delivery of interleukin 2 or 12. Finally, treatment with herpes simplex virus thymidine kinase/ganciclovir in combination with interleukin 2 was found to be superior over either treatment alone. This review discusses the various gene therapeutic approaches applied to MTC treatment in detail, gives an overview on the diverse vector systems used to achieve efficient transduction of thyroid cancer cells, and points out the strategies employed to accomplish target cell selective gene expression thereby contributing to enhanced safety of gene therapy for MTC

Animals↗
PubMed1982

Development of resistance to MOPC-315 plasmacytoma after intralesional and intraperitoneal melphalan therapy of tumor-bearing BALB/c mice. I. Enhancement of in vivo rejection responses by combined chemotherapy-immunotherapy.

Experimental and clinical evidence indicates that some chemotherapeutic agents may enhance tumor cell immunogenicity. This study was undertaken to test the possibility that melphalan [L-phenylalanine mustard (L-PAM)]--a clinically useful drug--can modulate tumor cells in vivo and in vitro in a syngeneic experimental system of MOPC-315 plasmacytoma in BALB/c mice and that this modulation can be expressed in vivo by enhanced tumor resistance. Tumor-bearing mice were treated with L-PAM intralesionally and ip by a split-course chemotherapy to avoid excessive toxicity of the drug. As a result of this treatment, about 60% of the mice had complete tumor regression; of these, 40-60% were resistant to viable tumor cell challenge and were designated as "cured-immune." Immunogenicity of irradiated MOPC-315 was tested in BALB/c mice; significant protection against tumor cell challenge was not achieved. In vitro L-PAM-treated MOPC-315 cells induced a measurable but weak antitumor response. Combination of both therapeutic approaches, i.e., chemotherapy and active immunization by L-PAM-treated tumor cells, was attempted with the use of various schedules. Immunotherapy given after L-PAM-induced tumor regression significantly enhanced in vivo antitumor response to challenge by 10(4) and 10(5) viable MOPC-315 tumor cells. When immunotherapy was attempted before chemotherapy in the presence of actively growing though still occult tumor, it reduced the chemotherapy cure rate and resulted in a low rate of tumor resistance. Addition of BCG did not remarkably affect the results. The findings point to the importance of timing of active immunization relative to tumor load and chemotherapy. The implication is that chemotherapy-induced regression is mediated by host immune mechanisms in this experimental model.

Animals↗
PubMed1992

Lymphocyte migration to tumors after hyperthermia and immunotherapy.

We have previously shown that the combination of immunotherapy with interleukin 2 (IL-2) and local hyperthermia (LHT) abrogates the growth of murine subcutaneous tumors significantly more than either modality alone. This study was undertaken to investigate whether the beneficial effect of combined modality therapy could be attributed to increased trafficking of effector cells to the tumor. After inducing MCA-105 sarcomas in the hindlimbs of C57BL/6 mice, animals were given no therapy, LHT, IL-2, or IL-2 + LHT followed by an iv injection of 51Cr-labeled syngeneic splenocytes or LAK cells. Select organs and the tumor-bearing extremity were counted in a gamma counter. IL-2 or LHT alone did not affect lymphocyte migration, while IL-2 + LHT significantly decreased trafficking (P less than 0.001) to the tumor. LAK cells showed increased migration to the tumor site compared to splenocytes in all treatment groups (P less than 0.02). IL-2 caused increased migration of LAK cells but not splenocytes to the lung; this was not affected by LHT. LAK cell trafficking to the spleen was decreased by IL-2 and IL-2 + LHT, while splenocyte migration was decreased in the LHT and combined treatment groups. LHT and IL-2 had no effect on trafficking of either effector cell type to liver or kidney. These results show that the beneficial effect of combined modality therapy may not be due to increased trafficking of lymphocytes to the tumor area. In addition, LAK cells traffic more to subcutaneous tumors than splenocytes, and this cannot be explained by the differential trafficking to other organs. The results of this study will be important in the planning of future experiments with combined adoptive immunotherapy and hyperthermia.

Animals↗
PubMed1990

Combination chemo-immunotherapy: kinetics of in vivo and in vitro generation of natural killer cells and lymphokine-activated killer cells in the rat.

Rats received a single high dose of cyclophosphamide (Cy) (150 mg/kg), followed 48 h later (on day 0) by immunization with a T cell-dependent soluble antigen, ovalbumin in Freund's complete adjuvant (FCA). The effect of this treatment on lymphoid cell subpopulations in the spleen, natural killer (NK) cell and interleukin-2 (IL-2) induced lymphokine-activated killer (LAK) cell activity was examined. Cy (with and without ovalbumin) caused a large relative increase (by day 14) in splenic OX8+, OX19- cells with NK morphology. A marked relative increase in fresh NK cell activity was noted after Cy + ovalbumin, but not consistently after Cy alone. Elevated NK activity was Cy dose- and time-dependent, was evident within 7 days post Cy/ovalbumin and persisted for at least 28 days. Pooled splenic mononuclear cells (MNC), obtained 14 days after Cy/ovalbumin, lost all cytolytic activity against YAC-1 cells when cultured in the absence of human recombinant IL-2 (rIL-2). In contrast, similarly maintained cells from normal rats displayed NK activity higher than normal 'fresh' levels. Upon culture in medium containing 500 U/ml rIL-2, however, 'augmented' NK activity was equivalent, on a per-cell basis, in both normal and Cy/ovalbumin-pretreated groups. LAK activity generated in vitro (i.e. against NK-resistant target cells) was significantly lower in the latter group, and the overall yield of cells was reduced. By day 21 after Cy/ovalbumin, augmented NK activity was significantly greater than controls, on a per-cell and total culture yield basis. Moreover, LAK activity was now similar between groups. It is concluded that the chemotherapy/immunization protocol which we have used can greatly enhance NK activity in vivo and that these cells are responsive to induction of LAK activity by IL-2 in vitro.

Animals↗