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Compositions and methods for treatment of tumors and metastatic diseases

a tumor and metastatic disease technology, applied in the field of tumor and metastatic disease compositions and methods, can solve the problems of inability to cause disease, low and insufficient immunogenicity of tumor antigens to induce more than occasional immune responses, so as to achieve effective treatment and accelerate tumor growth

Inactive Publication Date: 2002-04-04
FALKENBERG FR W
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0061] Another object of the present invention is to provide methods of preparing tumor vaccines capable of stimulating immune responses to tumor cells which are simple, reliable, and relatively inexpensive to use.
[0192] (b) The lower the amount of AL that is used to adsorb a certain amount of cytokine, the lower the percentage of the cytokine actually adsorbed to AL, but the higher the release rate and the shorter the release time.

Problems solved by technology

Although Freund's adjuvant is toxic and not used for immunization of human beings, mineral adjuvants such as aluminum hydroxide are common in human medicine.
The cells so irradiated are thus capable of promoting an immune response, but they are not capable of causing disease.
One of the problems presented by the treatment of human cancers with vaccines, however, is that the immunogenicity of tumor antigens is relatively low.
In general, tumor antigens are not sufficiently immunogenic to induce more than occasional immune responses.
This is due to the many cellular divisions that they undergo which in turn leads to a rather chaotic genetic organization.
However, due to their slow growth and other unknown factors, the host's immune system gets accustomed to the more and more foreign-looking tumor cells and it does not react to them.
NDV, however, is not a conventional adjuvant.
However, it is acknowledged that the induction of humoral immunity responses is or can be counterproductive--depending on the type of tumor--in tumor therapy.
On the other hand, it has also been shown that systemic therapy with cytokines can be extremely toxic, thus limiting its effectiveness.
Furthermore, it is known that "determining the best cytokine or cytokines to use is difficult because so many cytokines have the potential to augment immunity and because virtually all of the cytokines tested in mice have shown some potential usefulness."
It is known that administration of IL-2 to patients is often associated with adverse effects, sometimes so severe that the therapy must be halted.
The complications include the development of severe vascular permeability which leads to interstitial pulmonary edema and eventual multiorgan failure if the therapeutic administration of IL-2 is not reduced or discontinued.
In addition, patients may develop antibodies against IL-2 that could compromise therapy.
Although cytokines may play crucial roles in therapeutic vaccines for cancer treatment, these observations require a call for caution "because cytokines have as much potential to stimulate tumor growth as to retard it, and many cytokines effectively suppress immune responses under some conditions"; it is further acknowledged that these "complexities can only be unraveled by additional animal studies and direct testing in humans of promising candidate cytokines."
Although systemic application of rIL-2 demonstrated promising therapeutic effects, severe and occasional lethal side effects were produced.
In addition, the costs associated with this therapy can be very high.
The severe side effects may be due to the magnitude of the systemic doses of cytokines which must be administered to achieve the therapeutic benefits.
Systemic delivery of a cytokine, however, results in "flooding" of the entire organism with concentrations which would normally be present only at a localized cellular level.
Consequently, immune system cells cannot locate the source of the cytokines that were released upon reaction with the antigenic material, which may further lead to the suppression of the beneficial effects of cytokines or even to the failure of the immune system.
Other attempts to localized administration, however, have been less successful.
In addition, the very short half-life of cytokines in blood results in a very short period of activity.
Concisely, the administration of cytokines may lead to complications and deleterious effects.
Over a period of time, typically 1-2 weeks, however, the tumor begins to diminish and eventually disappears entirely.
Despite the promising results with cytokine-gene-transfected cells in experimental animals, adaptation of these methods to patients faces several hurdles.
As an initial matter, the technical difficulty and cost of generating sufficient quantities of gene-transfected tumor cells from a primary tumor specimen is significant.
This is a tedious and often unsuccessful procedure.
Thus, the overall procedure is time- and cost-intensive and the results can be unpredictable.
Another problem arises because the administration of viable gene-transfected tumor cells to patients is risky and ethically unacceptable.
Administration of cytokine-gene-transfected somatic cells such as fibroblasts is also risky.
Although the irradiated cells retain the capability of secreting the encoded cytokine, production capacity is often diminished.
With respect to irradiated transfected tumor cells, the combination of diminished capacity to produce the encoded cytokine and the elimination of viable, replicating cytokine-producing cells will severely limit the quantity of cytokines secreted.
In sum, the use of cytokine gene-transfected cells permits the localized delivery of cytokines but it has several drawbacks which include: unpredictability of the number of gene copies introduced in the transfected cell and extent to which the gene copies are expressed; unpredictability of the amount of cytokine that will be secreted by the transfected cells; and finally possibility that the transfected tumor cells will lose the inserted gene, escape elimination and develop new tumors.
In general, and despite the progress in gene therapy, the obtention of appropriately transfected cells is complicated, difficult, and expensive.
Notwithstanding the intense effort expended in research directed to the preparation of tumor vaccines capable of stimulating immune response to specific tumor antigens, none have been developed which are simple, reliable and relatively inexpensive.
As a result, efforts to develop such vaccines continue unabated.

Method used

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  • Compositions and methods for treatment of tumors and metastatic diseases
  • Compositions and methods for treatment of tumors and metastatic diseases
  • Compositions and methods for treatment of tumors and metastatic diseases

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0202] Therapeutic Vaccination Experiment

[0203] Renal carcinoma was induced into mice via intraperitoneal injection of a lethal dose of vital carcinoma cells to test the influence of tumor cell dose on survival. Four days later, the mice were vaccinated with the compositions described in the first column of Table 2.

2 TABLE 2 vaccination group n day -4 day 0 1 10.sup.6 RenCa 10 .mu.g IL-2 AL 8 i.p. tumor induction s.c. vaccination 2 10.sup.5 RenCa 10 .mu.g IL-2 AL 8 i.p. tumor induction s.c. vaccination 3 10.sup.4 RenCa 10 .mu.g IL-2 AL 8 i.p. tumor induction s.c. vaccination 4 10.sup.3 RenCa 10 .mu.g IL-2 AL 8 i.p. tumor induction s.c. vaccination 5 10.sup.2 RenCa 10 .mu.g IL-2 AL 5 i.p. tumor induction s.c. vaccination 6 10 .mu.g IL-2 AL 5 i.p. tumor induction s.c. vaccination 7 10.sup.6 RenCa 5 i.p. tumor induction s.c. vaccination 8 Medium (RPMI 1640) 5 i.p. tumor induction s.c. injection

[0204] Vaccination groups 1-4 were composed of 8 mice each and vaccination groups 5-7 compris...

example 3

[0220] Therapeutic Vaccination Experiment

[0221] The number of tumor cells plays a role in the composition of the vaccination preparation and also in the composition of the tumor induction preparation. The tumor cells are inactive in the vaccination preparation and the effect of the number of inactivated tumor cells in therapeutic vaccination has been analyzed in Example 2. The tumor cells are active a or vital (hereinafter "vit") in the tumor induction preparations of the therapeutic vaccination study in this example. The number of tumor cells used to induce a tumor is hereinafter referred to as "tumor burden".

[0222] As shown in Table 3, the vaccination groups comprised 10 mice each. The amount of vit B16 cells used to induce tumors were about 10.sup.4, about 10.sup.3 and about 10.sup.2. Mice with tumors induced by each one of these preparations were therapeutically vaccinated with preparations that comprised about 10.sup.5 inactivated B16 cells alone or about 10.sup.5 inactivated B...

example 4

[0241] Prophylactic Vaccination Experiment

[0242] The influence of the number of inactivated tumor cells in the vaccination composition on survival is analyzed here in a B16 prophylactic study. Prophylactic vaccination was administered four times prior to day 0 (hereinafter "challenge day") when the mice were subcutaneously injected a dose of tumor inducing preparation. Specifically, the prophylactic vaccinations were administered four times (4.times.) on days 35, 28, 21, and 14 prior to the challenge day. The control group comprised 5 mice that were subcutaneously injected medium on the same vaccination days that the mice in the vaccination groups were subcutaneously injected the corresponding vaccination preparation. Vaccination group 1 comprised 8 mice, and the vaccination preparation included about 10.sup.5 inactivated B16 cells, and about 10 .mu.g IL-2 adsorbed to about 10 .mu.g of aluminum hydroxide depot. Vaccination groups 2 and 3 comprised 6 mice each. The vaccination prepar...

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Abstract

Compositions and methods are provided which can be utilized in active immunization as a prophylactic treatment or a therapeutic treatment for tumors. The compositions are employed as injectable tumor vaccines or as preparations for intratumoral administration and are capable of stimulating immune responses to specific tumor antigens. The tumor vaccines are composed of an antigenic cellular material including a plurality of inactivated tumor cells or tumor cell portions, a depot material, and an immunostimulant adsorbed to the depot material. The depot material with absorbed immunostimulant is mixed with the tumor cells or tumor cell portions to form the vaccine compositions. The preparations for intratumoral administration include the depot material adsorbed immunostimulant without the antigenic cellular material. The immunostimulant adsorbed to the depot material permits release of biologically active quantities of the immunostimulant over a period of time rather than all at once.

Description

[0001] The present application is a continuation-in-part of U.S. application Ser. No. 08 / 538,730 filed on Oct. 3, 1995.[0002] 1. The Field of the Invention[0003] The present invention is directed generally to methods and compositions for active specific immunotherapy of tumors. More specifically the present invention is related to methods and compositions for treating tumors with vaccines and with preparations for intratumoral injections and to methods for preparing tumor vaccines and preparations for intratumoral injections that are capable of stimulating immune responses to specific tumor antigens.[0004] 2. The Relevant Technology[0005] Basic terminology and general principles in immunology. The foundation of immunology theory rests on the basic idea of self / non-self discrimination, a process that is accomplished by means of recognition mechanisms. Because these recognition mechanisms are used for defeating undesirable microorganisms and for eliminating potentially harmful substan...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00
CPCA61K39/0011A61K2039/5152Y10S514/965A61K2039/55522Y10S514/963A61K2039/55505A61K2239/31A61K2239/38A61K2239/56A61K39/461A61K39/4644
Inventor FALKENBERG, FRANK W.KRUP, OLIVER C.
Owner FALKENBERG FR W
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