Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-05-19
2003-09-09
Fredman, Jeffrey (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093100, C424S093210, C424S093710, C435S325000, C435S363000, C435S366000, C435S372000, C435S372100, C435S375000, C435S383000, C514S002600
Reexamination Certificate
active
06616925
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to a new combined preparation for the treatment of neoplasic diseases or of infectious diseases.
The present invention describes sequences of conventional treatments of cancer or infections and of immunotherapies reversing or preventing chemoresistance and allowing long lasting therapeutic responses.
2. Description of the Related Art
In conventional therapy, residual tumor cells or infectious agents are left undamaged due to chemoresistance or due to the fact that these cells are shaded in protected areas or located in hypoxic areas poorly vascularized and not accessible to conventional treatments. The genetic instability and heterogeneity of tumors and micro-organisms indeed allow them to adapt and to develop resistance to therapies.
The beneficial effects of chemotherapy can be compromised by cellular mechanisms that allow infectious agents or neoplasic tissue to evade the toxicity of drugs. In some cases, pleiotropic resistance to a variety of unrelated drugs has been observed, and this phenomenon has been called multidrug resistance.
Resistance to chemotherapy, whether it is intrinsic or acquired, is a major cause of failure in the curative treatment of chronic infections or neoplasic malignancies. Among the most active anti-cancer agents used in the treatment of haematological malignancies are some natural toxin-derived drugs, such as the anthracycline daunorubicin or adriamicin, the epipodophyllotoxins, taxoter derivatives, the vinca alkaloid vincristine, cisplatin, fluorouracils.
Development of cross-resistance to these structurally and functionally unrelated drugs, called multidrug resistance, is frequently observed in second or third intention cytotoxic treatment of cancer.
Multiple drug resistance of infectious agents and particularly of bacteria to antibiotics such as penicilins, &bgr;-lactamines, cephalosporines, aminoglucosides, macrolides and sulfamides, is more and more often seen in hospitals.
Monocytes derived cells (MDCs) are immune cells such as obtained by culture of blood mononuclear cells in non adherent gas permeable plastic or Teflon bags for 5 to 10 days at 37° C. in O
2
/CO
2
atmosphere. Their culture medium (RPMI, IMDM, AIM5 (Gibco) or X-VIVO (Biowhittaker)) contains eventually cytokines or ligands as defined in patents n
o
PCT/EP93/01232, n
o
WO94/26875 or EP 97/02703 or in the articles mentioned below:
“Autologous lymphocytes prevent the death of monocytes in culture and promote, as do GM-CSF, IL-3 and M-CSF, their differentiation into macrophages”. (Lopez M., Martinache Ch., Canepa S., Chokri M., Scotto F., Bartholeyns J.; J. of Immunological Methods, 159: 29-38, 1993);
“Immnune therapy with macrophages: Present status and critical requirements for implementation” (Bartholeyns J., Romet-Lemonne J-L., Chokri M., Lopez M.; Immunobiol., 195: 550-562, 1996);
“In vitro generation of CD83
+
human blood dendritic cells for active tumor immunotherapy” (Thurnher M., Papesh C., Ramoner R., Gastlt G. and al.; Experimental Hematology, 25: 232-237, 1997);
“Dendritic cells as adjuvants for immnune-mediated resistance to tumors” (Schuler G. and Steinman R. M.; J. Exp. Med., 186: 1183-1187, 1997).
All these patents applications and articles are included herein for references.
They can be activated by INF-&ggr; at the end of culture to obtain in particular cytotoxic macrophages. They can be centrifuged to be concentrated and purified before resuspension in isotonic solution.
Monocytes derived cells (MDCs) can either be killer macrophages, phagocytozing cells, growth factors and cytokines releasing cells, or dendritic cells according to their conditions of differentiation. Dendritic cells can for example be obtained as described in “In vitro generation of CD83
+
human blood dendritic cells for active tumor immunotherapy” (Thurnher M., Papesh C., Ramoner R., Gastlt G. and al.; Experimental Hematology, 25: 232-237, 1997) and “Dendritic cells as adjuvants for immune-mediated resistance to tumors” (Schuler G. and Steinman R. M.; J. Exp. Med., 186: 1183-1187, 1997), and EP n
o
97/02703.
In addition, activated monocyte derived cells (macrophages) can be used to deliver therapeutic agents to tumor or infectious sites.
SUMMARY OF THE INVENTION
One of the aims of the invention is to provide a combined preparation of active substances under the form of individual components for the simultaneous separate or sequential use, in the treatment of cancer or of infectious diseases.
Another aim of the invention is to provide a method for the treatment of residual cancer resistant to chemotherapy.
Another aim of the invention is to provide a method for the treatment of infectious diseases resistant to antibiotic treatment.
The invention relates to a combined preparation containing, as active substance, the following individual components, in the form of a kit-of-parts:
monocyte derived cells, particularly cytotoxic macrophages,
chemotherapy or immunotherapy drugs,
for the simultaneous, separate or sequential use, for the treatment of cancer or infectious diseases.
The present treatment consists in the local or systemic injection of autologous activated macrophages (MAK® killer cells) or monocyte derived cells which have access to injured areas, and in particular to hypoxic areas, where they tend to concentrate.
This treatment can be conducted after first failure and relapse following chemotherapies, or before chemotherapy, to prevent chemoresistance. Local treatment with chemotherapy drugs causes cell necrosis and release of chemokines which call and actively recrute macrophages and monocytes derived cells. Therefore, combining the chemotherapy with macrophage immunotherapy can in synergy increase cytotoxicity and increase immune response at the same time as preventing the establishment of resistance. Additionally to a first treatment combining conventional approach with immunotherapy, macrophage adoptive therapy can be proposed after failure and relapse.
It is shown through the invention that the local or systemic injection of activated monocyte derived cells, or macrophages, restores clinical responses to cytotoxic drugs for which resistance was previously demonstrated, or prevents the apparition of chemoresistance.
The present invention also shows that activated monocyte derived cells can overcome this resistance and synergize for therapy.
The two active ingredients of the combined preparation have never been used for a new joint effect and are unknown as a composition.
The active ingredients which are administered either at the same time, or separately, or sequentially, according to the invention, do not represent a mere aggregate of known agents, but a new combination with the surprising valuable property that immunotherapy with monocyte derived cells modifies the chemoresistance/chemosensitivity and allows a new effective treatment (partial or complete response) with similar chemotherapy protocole. Furthermore, synergy is observed between monocyte derived cells immunotherapy and chemotherapy.
It is to be stressed that the combined preparation also designated by a kit-of-parts means that the components of the combined preparation are not necessarily present as a union e.g. in composition, in order to be available for separate or sequential application. Thus the expression kit-of-parts means that it is not necessarily a true combination, in view of the physical separation of the components.
In an advantageous combined preparation of the invention, the monocyte derived cells contain chemotherapy or immunotherapy drugs.
In another advantageous combined preparation of the invention, the monocyte derived cells are such as prepared according to the method comprising the following steps:
1) recovery of blood derived mononuclear cells directly from blood apheresis or from blood bag collection, followed if necessary by centrifugation, to eliminate a substantial part of red blood cells, granulocytes and platelets, and collection of peripheral blood leukocytes;
2) washing peripheral blood leuko
Bartholeyns Jacques
Fouron Yves
Romet-Lemonne Jean-Loup
Fredman Jeffrey
I.D.M. Immuno-Designed Molecules
Kaushal Sumesh
Young & Thompson
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