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European Biopharmaceutical Review

Body of Evidence

In the fight against cancer, the greatest weapon we have is our body, with Biological Response Modifiers moving us one step further in the future of therapeutic medicine

Modulating our immune system response to tumours through so-called Biological Response Modifiers (BRMs) is a powerful approach in the cancer treatment landscape. There are excellent reasons for the current excitement, since molecules such as monoclonal antibodies or vaccines confer specificity when attacking the tumour cells. In addition, BRMs have the ability to create an anti-tumour immunological memory, and to stimulate our body to fight against the malignancy that emerged from it in the first place.

The National Cancer Institute from the National Institutes of Health defines biological cancer therapies as ones that modulate the body’s immune system to fight cancer. This modulation is performed by BRMs that include molecules naturally produced by our own body, such as interferons, interleukins or monoclonal antibodies. Several other therapeutic approaches – such as vaccines, gene therapy or cell therapy – could also be considered as BRMs.

Anti-tumour effects of BRMs can be both direct, when BRMs either have direct cytotoxic effects on tumour cells or directly impede tumour proliferation and survival; and indirect, when BRMs either influence the immune response to eliminate cancer cells or alter essential processes for cancer progression such as tumour angiogenesis.

Monoclonal Antibodies

Monoclonal antibodies (mAbs) are large proteins produced by the immune system to identify and label foreign invaders. Since tumour cells show a different phenotype compared to normal healthy cells, antibody-based therapy relies on the ability of mAbs to recognise these subtle differences.

mAbs are designed to detect and bind to a specific antigen of the tumour cell. Once the target cell is labelled, the mAbs can trigger a variety of mechanisms to destroy the malignant cell. On the one hand, mAbs can directly modulate the immune response. mAbs such as Rituximab can provoke the elimination of tumour cells by triggering immune system mediated mechanisms like B cell activation; another example of direct modulation of the immune response is the mAb Ipilimumab, which by blocking the CTL-4-mediated T-cell repressing signal, enhances the immunological anti-tumour response (1).

On the other hand, mAbs are also able to directly block survival signalling cascades, as well as to induce apoptotic pathways in the tumour cells. Some examples of therapeutic mAbs using these mechanisms are Cetuximab or Trastuzumab (2). In addition, mAbs such as Gemtuzumab are used as carriers of cytotoxic molecules that are specifically delivered to tumour cells to eliminate them (3). Finally, mAbs like Bevacizumab can block biological processes that are essential for cancer progression, such as the induction of vascularisation (inhibiting the VEGF signalling) or the attachment to distant tissues and metastasis (4).

There are currently over 15 mAbs approved for cancer therapy by the various regulation authorities around the world. Furthermore, hundreds of clinical studies are currently under way trying to develop the next generation of specific mAbs that will lead the fight against cancer (5).

Interleukins
Interleukins (ILs) are a group of over 30 cytokines that are key signalling molecules to modulate inflammation and immunity. They induce proliferation, activation, migration and differentiation of immune cells. Contrary to mAbs, the anti-tumour effect of cytokines is non-specific.

The most significant case is interleukin-2 (IL-2), the first-ever immunotherapy approved by the Food and Drug Administration and nowadays indicated for the treatment of several malignancies including melanoma, kidney cancer and leukemia. By modulating the homeostasis of T cells, IL-2 is essential in the establishment of the immunologic memory, as well as in the identification by the immune system of self and non-self (6).

Various ILs are currently being tested for cancer treatment in a variety of clinical assays both alone or in combinational therapies as adjuvants, including in the brain, prostate and colorectal cancers, leukaemia and lymphoma (5).

Interferons
Interferons are another group of cytokines produced by cells in response to pathogen infection and malignant transformation. Their anti-tumour effects are either direct on the target cells, by reducing protein synthesis and blocking its cellular proliferation; or indirect, by enhancing the response of the immune system against the transformed cell and its elimination, as well as by blocking tumour angiogenesis.

Interferon-alpha is the only interferon type approved for cancer treatment. It is being used for the treatment of several cancers including: renal cell carcinoma; multiple myeloma; and some types of leukemia (7). In addition to the many ongoing clinical trials testing interferonalpha as the therapeutic agent (alone or in combination) in various cancers including kidney, lung or bladder, there are several other studies now testing interferon-beta, including one protocol of gene therapy in liver cancer (5). Finally, the recently described interferon lambda has shown a significant anti-tumour activity in preclinical studies, envisioning a promising future in cancer therapy since it only acts in a small fraction of cells potentially, showing fewer sideeffects than current interferon-based therapy (7).

Colony-Stimulating Factors

A third group of cytokines – colonystimulating factors (CSFs) – are produced and secreted to stimulate the division of bone marrow stem cells and their differentiation into specific blood cells (platelets, white cells or red cells). Their administration induces blood cell production, which in turn is highly beneficial for cancer patients since their blood cell count is severely damaged by most current cancer therapies. Therefore, CSFs are prescribed mainly as adjuvants to reduce the side-effects associated to cancer treatment toxicity.

Several CSFs are currently being used in cancer therapeutic protocols tumours of the uterus, lung, esophagus and many others. Some highlighted examples of used CSFs are: the granulocyte CSF, filgrastim, and the granulocyte macrophage CSF, sargrasmostin, which stimulate the formation of white blood cells and significantly reduce the risk of infection and sepsis for cancer patients; the erythropoietin known as epoetin, which increases the number of red cells, consequently reducing the incidence of anemia; and interleukin 11 that stimulates megakaryocyte maturation and platelets production, reducing the need of platelets transfusions (8-10).

Cancer Vaccines

Following the same biological principles used by anti-pathogens vaccines, the aim of cancer vaccines is to educate the immune system into the recognition of tumour cells for their elimination. The ultimate goal is to develop vaccines that are able to induce long-lasting and powerful T-cell responses with the capacity of generating immunological memory.

Most of the cancer vaccines are administered after the tumour is diagnosed. There are only two preventive cancer vaccines currently available: the vaccine that prevents the infection of the hepatitis B virus, which causes 80 per cent of all primary liver cancers (11); and the vaccine that blocks the appearance of cervical cancer provoked by the infection of human papilloma virus (12).

The only approved therapeutic vaccine is Sipuleucel-T, which is based on the use of the patient’s own white blood cells and is designed for prostate cancer (13). Although no antigen-based therapeutic vaccine has reached the market yet, various approaches are being developed by investigators. There are several clinical trials showing success in late clinical phases for the treatment of several tumour malignancies including follicular lymphoma, non-small cell lung cancer and prostate cancer (5).

Cellular Immunotherapy

Dendritic Cells
Dendritic cells (DCs) have the main function of processing and presenting antigens to lymphocytes. DCs play a crucial role in presenting tumour antigens to T-cells, in this way initiating the immune response against cancer. The usage of DCs as anti-cancer treatment is based on the development of cancer vaccines. The haematopoietic progenitors of DCs are extracted from the patient and cultured ex vivo in the presence of cytokines and tumour-specific antigens. Cultured matured DCs are re-injected into the patient and will migrate to the lymphnodes to present the tumourantigen to T-cells to trigger the antitumour immune response (14). There has been over 200 clinical trials with DC vaccines, and many trials are currently being opened to develop DC-based vaccines to treat various indications, including colorectal, kidney or head and neck cancers (5).

T-Cells
Antigen presentation by specialised cells, including DCs, activate the T lymphocytes which will mediate the tumour-specific immune response to eradicate the malignant cells. T-cells can be used in cancer immunotherapy following two main approaches. On one side, T-cells residing in the tumour can be isolated from a biopsy and expanded ex vivo. Once grown, these tumour-specific T-cells are infused into patients in a therapeutic regime accompanied with immunodepletion of the patient. This approach has been shown to be effective in clinical studies in the treatment of metastatic melanoma (15).

An additional approach is based on the genetic engineering of T-cells prior to patient infusion so they overexpress a specific T-cell receptor (TCR) with high affinity and specificity to a given tumour target antigen. There are several ways to accomplish the overexpression of a specific TCR in the lab. The most common consists of isolating T-cells residing in the tumour and infecting them ex vivo with a lab-generated vector virus encoding the desired TCR. Once these activated T-cells expressing the TCR are expanded, they can be infused into the patient to potentiate the specific anti-tumour immune response (15).

T-cell based immunotherapy – in particular, the genetic engineering approach – is one of the most promising biological therapies for cancer as a subtype of the promising field of gene therapy. In accordance to its relevance and potentiality, many clinical trials are using this approach to evaluate its anti-tumour effects including prostate, breast and liver cancers as well as leukemia and lymphoma (5).

Natural Killer Cells

Similarly to T-cells, the natural killer (NK) cells and the natural killer T (NKT) cells are able to identify tumour cells and target them for elimination. Their killing capacity is kept under control through a delicate balance between a complex network of repressive and activating signals that normal cells are able to regulate with perfection. However, tumour cells tilt the balance by either losing the repressing signalling or upregulating the activating cascades.

They are currently being applied in cell therapy protocols in which either the whole haematopoietic stem cell population or laboratory-expanded populations of isolated NK/NKT cells are transplanted from a matching donor to the cancer patient (16).

Conclusion

The field of biological therapies is one of the most active and promising in cancer treatment. Both the tumour specificity and its capacity to generate anti-tumour memory are powerful presentation credentials for a therapeutic approach that possesses the solid foundation of decades of clinical studies behind it. It has the potential to become a reference in the future of medicine comprising gene and cell therapies, as well as personalised medicine.

References

1. Scott AMK et al, Antibody therapy of cancer, Nat Rev Cancer 278,12: pp278-287, 2012

2. Hudis CA, Trastuzumab-mechanism of action and use in clinical practice, N Engl J Med, 357: pp39-51, 2007

3. Niculescu-Duvaz I, Technology evaluation: gemtuzumab ozogamicin, Celltech Group, Curr Opin Mol Ther, 2(6): pp691-696, 2000

4. Ferrara N et al, Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer, Nat Rev Drug Discov 3(5): pp391-400, 2004

5. Visit: www.clinicaltrials.gov

6. Smith KA, Interleukin-2: inception, impact, and implications, Science 240(4856): pp1,169-1,176, 1988

7. Lasfar A et al, Interferon Lambda: A new sword in cancer immunotherapy, Clin Dev Immun: pp1-11, 2011

8. Crawford J et al, Final results of a placebocontrolled study of filgrastim in small-cell lung cancer: Exploration of risk factors for febrile neutropenia, Sup Cancer Ther 3(1): pp36-46, 2005

9. Fisher JW et al, Erythropoietin production by interstitial cells of hypoxic monkey kidneys, Brit Jou Hem 95(1): pp27-32, 1995

10. Paul SR et al, Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine, Proc Natl Acad Sci 87(19): pp7,512-7,516, 1990

11. King T et al, Comparison of the immunogenicity of hepatitis B vaccine administered intradermally and intramuscularly, Rev Infect Dis 12(6): pp1,035-1,043, 1990

12. Harper DM et al, Sustained efficacy up to 4.5 years of a bivalent L1 viruslike particle vaccine against human papillomavirus types 16 and 18: Follow up from a randomized control trial, Lancet 367: pp1,247-1,255, 2006

13. Plosker GL, Sipuleucel-T: in metastatic castration-resistant prostate cancer, Drugs 71(1): pp101-108, 2011

14. Palucka K and Banchereau J, Cancer immunotherapy via dendritic cells, Nat Rev Cancer 12: pp265-277, 2012

15. Restifo NP et al, Adoptive immunotherapy for cancer: harnessing the T cell response, Nat Rev Immunology 12: pp269-281, 2012

16. Vivier E et al, Targeting natural killer cells and natural killer T cells in cancer, Nat Rev Immunology 12: pp239-252, 2012


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Alex Casta is the Head of Technology Transfer and Innovation at Biocat and the Coordinator of the Catalan oncology network, Oncocat. Alex has a PhD in Molecular Biology of Cancer from Columbia University and an MBA from IESE Business School. After 10 years working as a basic researcher, he switched his career focus, working for several Catalan biotech companies in business-related roles, as well as being a consultant for the entrepreneurship and company creation department at the technology transfer office of the University of Barcelona.
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