Cancer immunotherapy using autologous tumor cells combined with cells expressing a membrane cytokine

Abstract

This invention comprises cellular vaccines and methods of using them in cancer immunotherapy, particularly in humans. The vaccines comprise a source of tumor-associated antigen, and a cytokine-secreting cell line. Tumor antigen may be provided in the form of primary tumor cells, tumor cell lines or tumor extracts prepared from the subject. In certain embodiments of the invention, the cytokine-secreting line is a separate tumor line that is allogeneic to the patient and genetically altered so as to produce a cytokine at an elevated level. Exemplary cytokines are IL-4, GM-CSF, IL-2, TNF-α, and M-CSF in the secreted or membrane-bound form. In these embodiments, the cytokine-producing cells provide immunostimulation in trans to generate a specific immune response against the tumor antigen. Vaccines may be tailored for each type of cancer or for each subject by mixing tumor antigen with a favorable number of cytokine-producing cells, or with a cocktail of such cells producing a plurality of cytokines at a favorable ratio.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of provisional U.S. Patent Applications 60 / 023,108, filed Jul. 25, 1996, pending; and 60 / 029,286, filed Oct. 29, 1996, pending. The afore-listed applications are hereby incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates generally to the fields of cellular immunology and cancer therapy. More specifically, it relates to the generation of an anti-tumor immune response in a human by administering a cellular vaccine, comprising cells genetically altered to secrete a cytokine, in combination with a source of tumor antigen. BACKGROUND [0003] In spite of numerous advances in medical research, cancer remains a leading cause of death throughout the developed world. Non-specific approaches to cancer management, such as surgery, radiotherapy and generalized chemotherapy, have been successful in the management of a selective group of circulating and sl...

AI Technical Summary

Problems solved by technology

In spite of numerous advances in medical research, cancer remains a leading cause of death throughout the developed world.

However, many solid tumors are considerably resistant to such approaches and the prognosis in such cases is correspondingly grave.

There is no cure, and virtually all patients ultimately succumb to recurrent or progressive disease.

The overall survival for grade IV astrocytomas (glioblastoma multiforme) is poor, with ˜50% of patients dying in the first year after diagnosis.

Although many of these patients initially respond to the standard combination of surgery and cytotoxic chemotherapy, nearly 90 percent develop recurrence and inevitably succumb to their disease.

Despite these experimental observations, systemic administration of ex vivo-stimulated autologous tumor-specific lymphocytes has not become part of standard cancer therapy.

This strategy is labor-intensive, costly, and not suited to all patients.

49:1441-1446 showed that A-LAK cells are superior to LAK cells at reducing lung and liver metastases of breast cancer in experimental animal models, but this was not curative and there were no long-term survivors.

While none of these trials was associated with serious clinical complications, efficacy was only anecdotal or transient.

Unfortunately, TILs can only be prepared in sufficient quantity to be clinically relevant in a limited number of tumor types.

Even though these initial experiments were conducted over a decade ago, the strategy has not gained general acceptance, especially for the treatment of solid tumors.

First, implantation is frequently performed by surgical techniques, which may be too invasive for routine maintenance.

Second, the strategy is directed at generating a local response, and may not be effective against metastases.

Finally, the techniques remain unproved for use in human therapy.

For patients with tumors that did not acquire expression of the antigen during malignant transformation, or that subsequently differentiated so as not to express it, none of these vaccines will be successful.

This approach does not solve the well-established observations that many tumors are not naturally immunogenic.

In addition, there is usually not enough time to genetically alter and grow up sufficient cells of the patient to be treated for use in a vaccine.

Many human cancers of widespread clinical interest do not have reliable commonly-shared markers.

Since the immune response would be focused only at the particular tumor-associated antigen used, it may be less effective than one directed against the spectrum of antigen expressed by a complete tumor cell.

Cohen demonstrated only a modest improvement in survival in the animal studies, and failed to provide any evidence that his formulation would be effective in human cancer patients.

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