Immunology concepts and applications

Cancer Immunotherapy

We are at the threshold of new and entirely different approach to the management of cancer. Many multi-antigenic cancer vaccines are now in the last phase of clinical trials. Personalized cancer treatment in the form of adoptive T cell therapies, and entirely different perspectives in research such as 'Tregs suppression' have added more strength to our fight against cancer.

Since the discovery of the anti-cancer properties of interleukin-2 in 1976, much progress has been achieved in the field of cancer immunotherapy. [Steven Rosenberg]. The rapid strides achieved in the fields of molecular biology and immunology have greatly enhanced our understanding of tumor mechanisms. We are at the forefront of developing new and effective methods of fighting against cancer. Besides the prolonged efforts for developing multi-antigenic cancer vaccines, research has also progressed much in cell transfer therapy including adoptive T cell therapy and chemokine therapy. A brief overview of the developments in various immunotherapeutic treatment modalities would shed more light on the subject.

Immunotherapy for Cancer

Recent developments in biotechnology and the increasing understanding of molecular biology have made possible to test and develop new immune pathways to the destruction of cancer cells. Two major classes of T. lymphocytes (CD4 and CD8) have been known for their anti-cancer properties. Studies have also revealed that the CD4 and CD8 T. lymphocytes identify more than 3 dozen antigens. [Steven Rosenberg] Studies have shown that tumor specific antigens are able to trigger the body's innate anti-inflammatory responses and hence invoke natural immune reaction. One recent study has confirmed the direct link between immune system and cancer. For this clinical study, a total of 905 patients who had undergone various organ transplantation surgeries were recruited. Since these patients were under immunosuppressive therapy (to prevent organ rejection), they were the ideal candidates for the research on immunosuppression and cancer. 102 of these subjects developed various forms of cancer that represents a very high ratio of 7.1 times that of the general population. The results of this study clearly support the immune surveillance theory that claims that the immune system actively detects and eliminates tumor cells. [Olivera J. Finn]

Three important criteria are necessary for the success of immune therapy against cancer. First is the presence of large number of 'tumor reactive lymphocytes' in the host, secondly these tumor reactive lymphocytes should be able to reach and be active at the tumor sites and finally they must possess effector mechanisms to destroy the tumor cells. Two important approaches in immunotherapy for cancer include the development of cancer vaccines and the cell transfer therapy.

Cell Transfer Therapy

Adoptive transfer of cytotoxic T. lymphocytes is one of the currently popular approaches in cancer immunotherapy. Also known as passive immunization, this technique involves the transfusion of autologus T cells into the cancer hosts to trigger immune reaction. This therapy is based on the fact that leukocytes derived from patients with advanced stages of cancer have tumor destroying properties. Currently, many different CTL (Cytotoxic T-lymphocytes) targets are available for different types of cancers. One research that studied the effects of infusion of Melanoma associated antigen MART-1 -- specific CD8+ T cells showed profound T cell activity in the patients. This was confirmed by elevated count of circulating T cells 2 weeks post treatment. However, the researchers also noticed that only 3 out of the 11 test patients showed tumor recovery signs. This is because of the antigen escape variations by the tumor cells. This could be better managed by developing a variety of antigen specific CTL clones for infusion that would in turn result in a broader T cell repertoire. [Carl H. June]

A study by Oikawa et.al (2002) found that the use of adoptive CTL monotherapy was very effective in a patient with recurrent renal carcinoma. Lymphocytes were isolated from the patient and cultured in vitro which were later injected back into the patient. Three such courses were administered. The patient showed partial response, which continued over two years clearly suggesting the efficacy of adoptive transfer of CTL in the treatment of renal cancer. [Oikawa et.al] it is hoped that this ability to extract and culture autologus lymphocytes ex-vivo and develop them with the potential to destroy tumor specific cells will create a more specific and effective treatment for tumors.

Chemokine Therapy

Recently, the role of chemokines, a small group of protein molecules that regulate leukocyte migration is the focus of therapeutic cancer research.. Chemokines have proinflammatory properties and are directly involved in leukocyte migration during the inflammatory process. Researchers feel that various chemokine receptors such as CXCR4, CCR4, CCR10 are involved in cancer metastatis. Currently there are 50 known chemokines. By using appropriate chemokine receptor antagonists, it is possible to control cancer angiogenesis. Since we have already developed CCR5 receptor antagonist for use against HIV, development of similar chemokine receptor antagonists for tumor is not a long way away. The use of CKR antagonists as adjuvant immunotherapy alongside regular treatment would greatly improve the prognosis for cancer patients. [Wu Xuesong, 2009] the adeno virus vector is currently the most popular mode of encoding chemokine genes for use in cancer immunotherapy. Results from some studies have shown significant antitumor activity. However, one big limitation with the use of AD vectors is that they have no effect in the case of tumor cells that do not express ad receptors. More advancements in the gene carrier technology is expected to make chemokine immunotherapy more effective. [Jian Quing ]

Cancer Vaccines

Development of cancer vaccine has been at the forefront of research over the last decade. As with other diseases, the body's ability to detect tumor antigens and the immune response triggered against these specific antigen-bearing cells is the focus of cancer vaccine research. This approach is logical in the case of virus-induced tumors such as lymphoma (Epstein Barr Virus), cervical Cancer (human papiloma virus) and liver cancer (Hepatitis B). However, the hindering fact in cancer vaccine research is the fact that most cancers are of unknown origin and having to deal with so many different antigens presents a complex task in the selection criteria for vaccine development. The testing of tumor specific antigens such as CEA (Carcinoembryonic antigen), MUC1 and Her2 (Human epidermal Growth factor) in mice have shown encouraging results with no autoimmunity. [Olivera J. Finn] However, clinical tests are still awaited for these antigen-based vaccines. Though we are significantly advanced in our understanding of tumor immunology, there has been very little success in terms of the therapeutic effects of cancer vaccines. as, Steven Rosenberg, one of the pioneers of cancer vaccine research reported, the treatment response was barely 3.3% in a comprehensive vaccine treatment program involving 1306 patients with metastatic cancer. [Kyogo et.al]

Peptide Vaccines

Over the last decade or so, a large body of clinical research has focused on the use of peptide vaccine for cases of cancer patients who are otherwise non-responsive to general therapy. However, an overview of these studies in peptide vaccines reveals that clinical response is only marginal. Hamid et.al (2007), a phase 2 trial of multiple melanoma peptide vaccine for advanced melanoma patients (stage 2 to 4) showed that patients who developed T cell response (n=34) to atleast one of the peptides in the vaccine had a longer disease free survival (DFS) compared to those who did not have any immune response (n=14). (P = 0.041). Another study by Bolonaki et.al (2007) showed that the use of telomerase reverse transcriptase (TERT) peptide vaccine in advanced cases of non-small cell cancer improved the overall survival rate (P = 0.012) in those patients who had a marked immune response (n=16) compared to those who did not respond to the vaccine. (n- 5). A study by Domcheck et.al found that the use of TERT peptide vaccine in HLA-A2 + metastatic breast cancer patients increased the median survival rate (P = 0.03). To 32. 2 months for the nine patients who responded to the vaccine compared to 17.5 months among the seven patients who failed to respond. [Kyogo et.al]

Dendritic Cell Vaccines

This is another important and developing technology in cancer vaccine research and it involves the culturing of autologus dendritic cells to use them to trigger immune response against the tumor cells. As potent antigen presenting cells, dendritic cells loaded with specific tumor-associated antigen (TAA) offer an excellent mechanism for triggering the host immune activity. Also, since the availability of major histocompatibility complex molecules is a necessary factor in the T cell activation pathway, dendritic cells which express MHC class 1 and MHC class 11 cells constitute an ideal choice for cell-based tumor vaccines. Currently, dendritic cells-based vaccines are being used in clinical trials mainly for melanoma patients. Results from these trials have shown dendritic vaccines to be effective only in a small number of patients.

The phase 3 clinical study conducted by the Dendrion Corporation revealed that the overall survival (OS) improved among those administered with the dendritic vaccine when compared to the placebo group. The MST (median overall survival) was 25.9 months in the experimental group while it was 21.4 months in the placebo group. (P=0.01) [Kyogo et.al] an earlier study by Nestle et.al (1998) had showed promising results. In that study, a small group of renal cancer patients were vaccinated with RNA-transfected dendritic cells. T cell response was noted in most of the treated patients and a follow up study conducted after 19 months showed that 7 out of 10 patients still survived. [Jian et.al, 2008] Other vaccines such as the 'Heat shock protein' (HSP) vaccine introduced in clinical trials have only showed mixed results and have not been responsive in all patients. Oncophage is one HSP that has been approved in Russia for renal cancer patients. [Kyogo et.al]

TREGS (a new outlook at Immunotherapy)

A relatively new and much less explored path in the immunotherapeutic research is the focus on the role of TREGS (regulatory T cells). All the techniques discussed above were concerned with boosting the host with additional T cells or tumor infiltrating Lymphocytes. However the results from these therapies have thus far only indicated marginal response. Hence, priming up the immune system may not be only solution to the problem. Also since tumors are intrinsic, any immunotherapy designed against it has the potential to cause autoimmune complications. Research has also shown that tumors evade the natural immunity by producing immunosuppressive factors such as IL-10 TGF-?, and VEGF. Therefore, immunotherapeutic research would be more effective if it also focuses on this immunosuppressive aspect of tumor. [Tyler J. Curial]