Human prostate cell lines in cancer treatment

Abstract

Combinations of cell lines are provided for allogeneic immunotherapy agents in the treatment of cancer. Cancer vaccines generally have been limited to the use of cells that contain at least some tumour specific antigens (“TSAs”) and / or tumour associated antigens (“TAAs”) having shared identity with antigens in a targeted tumour. In such cases, tumour cells often are utilised as a starting point on the premise that only tumour cells will contain TSAs or TAAs or relevance, and the tissue origins of the cells are matched to the tumour site in patients. A primary aspect of the invention is the use of immortalised normal, non-malignant cells as the basis of an allogeneic cell cancer vaccine. Normal cells do not posses TSAs or relevant concentrations of TAAs and hence it is surprising that, normal cells are effective as anti-cancer vaccines. More surprisingly, a three way combination of cells obtained from metastasised cells, non metastasised tumour and cells from a normal cell line provided good therapy. For prostate cancer, for example, a vaccine may be based on one or a combination of different immortalised normal cell lines derived from the prostate according to parameters described herein. The cell lines may be lethally irradiated with, for example, gamma irradiation at 50-300 Gy to ensure that they are replication incompetent prior to use.

Description

FIELD OF THE INVENTION The invention relates to the treatment of primary, metastatic, and residual cancer in mammals, and more particularly to the use of materials such as whole cells and derivatives and portions thereof to stimulate the immune system to attack cancer. BACKGROUND TO THE INVENTION Cancerous cells contain numerous mutations that can result in recognition of the cells by a host's immune system. Appreciation of this phenomenon has prompted much research into potential immunotherapies to harness the host's immune system for attacking cancer cells. Eliminating these cells or reducing them to a level that is not life-threatening has been a major goal, as reviewed in Maraveyas, A. & Dalgleish, A. G. 1997 Active immunotherapy for solid tumours in vaccine design in The Role of Cytokine Networks, Ed. Gregoriadis et al., Plenum Press, New York, pages 129-145; Morton, D. L. and Ravindranath, M. H. 1996 Current concepts concerning melanoma vaccines in Tumor Immunology—Immunothe...

AI Technical Summary

Benefits of technology

Another embodiment provides an allogeneic immunotherapy vaccine for the treatment of prostate cancer in a patient, comprising an adjuvant, allogeneic cells from a first normal prostate cell line, allogeneic cells from a second immortalized cell line obtained from a prostate cancer biopsy, and allogeneic cells from a third immortalized line obtained from a prostate cancer biopsy, wherein cells of the second immortalized cell line express normal levels of neutral endopeptidase but low levels of endothelin converting enzyme and cells of the third immortalized cell line express unusually low levels of both neutral endopeptidase and endothelin converting enzyme.

Problems solved by technology

Although successful in a limited number of cases (e.g. BCG (i.e. bacille Calmette-Guérin) for the treatment of urinary bladder cancer, IL-2 for the treatment of melanoma and renal cancer) it is widely acknowledged that non-specific immunomodulation is unlikely to prove sufficient to treat the majority of cancers.

While non-specific immune-stimulants may lead to a general enhanced state of immune responsiveness, they lack the targeting capability and also subtlety to deal with tumour lesions which have many mechanisms and plasticity to evade, resist and subvert immune-surveillance.

Originally hailed as the magic bullet because of their exquisite specificity, monoclonal antibodies have failed to live up to their expectation in the field of cancer immunotherapy for a number of reasons, (thereby abrogating their activity) including immune responses to the antibodies themselves and inability of the antibody to access the lesion through the blood vessels.

Although elegant in concept, the utility of antibody-based approaches may ultimately prove limited by the phenomenon of ‘immunological escape,’ where a subset of cancer cells in a mammalian or human subject mutates and loses the antigen recognized by the particular antibody and thereby can lead to the outgrowth of a population of cancer cells that are no longer treatable with that antibody.

Sequencing of the RNA has identified several TAA and TSA which are expressed in that specific tissue at that specific time, but therein lies the potential deficiency of the approach in that identification of the TAA or TSA represents only a “snapshot” of the lesion at any given time which may not provide an adequate reflection of the antigenic profile in the lesion over time.

The approach suffers from the same inherent weakness as differential display techniques in that identification of only one TAA or TSA may not provide an appropriate representation of a clinically relevant antigenic profile.

In a similar manner to that described for antibody-based approaches above, subunit vaccines also may be limited by the phenomenon of immunological escape.

However the commercial utility of these approaches are expected to be more than a decade away.

Although this approach enjoyed considerable attention over the past decade, it has been increasingly apparent that this individually-tailored therapy is inherently impractical for several reasons.

The procedure is time consuming as the lead time for producing clinical doses of vaccine often may exceed the patients' life expectancy.

The procedure may be expensive and, as a ‘bespoke’ product, it is not possible to specify a standardised product (only the procedure, not the product, can be standardised and hence optimised and quality controlled).

The characteristics of the initial cell sample, which reflect a particular environment at a single time point from a tumour may severely limit the use of autologous cells for immunotherapy:, wherein a vaccine desirably may be administered over the entire presentation time of a disease.

Despite this intensive work in a crucial field of medical science, successful and reproducible eradication or inhibition of cancer growth remains elusive.

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