The ideal goal of cancer vaccine is to elicit potent anti-tumour immune responses without any contributing side-effects. The major aim is to stimulate both innate and adaptive immunity that can recognise and subsequently eliminate the tumours mass. Cancer immunotherapy continues to be a field of intense research, especially the induction of active immunity.
The existence of tumour-specific antigens (TSAs) that can be the targets for an immune response is well established [3]. Advances in cancer genomics anticipate an even greater array of potential TSA targets.
Anti-tumour Immunity
It is well established that the immune system has capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes converting them vulnerable to immune cells. Yet, it is self-evident that a growing tumour has managed to evade the host defense mechanisms. The exact ways in which the immune system interacts with tumour tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully explained.
The T-cell immune response can be broken down into the following steps. All of the steps need to be satisfied for effective anti-tumour immunity:
(1) tumour antigen(s) must be present, and
(2) they must be seen as dangerous by the immune system;
(3) antigens must be acquired and presented by antigen presenting cells (APC) in the draining lymph node;
(4) specific T-cells must then recognize and respond to tumour antigen by proliferation, enter into systemic circulation and reach to the tumour site as CTL;
(5) where they need to overcome the local immunosuppressive environment before killing tumour cells.
In addition, the memory cells may need to be generated to produce a long-lasting response. It is clear that a growing tumour has managed to escape this process. Failure of the anti-tumour immune response can occur at one or more of these steps. Targeting rate limiting steps with therapies designed to boost the immune response can improve anti-tumour immunity.
Tumour Antigens
Tumours typically express two types of antigen: neoantigens and self-antigens. Neo-antigens (tumour-specific antigens) are derived from mutated self-proteins that are not expressed in normal tissues. Malignant cells express numerous neo-antigens as a result of genomic instability.
Most of these mutations do not have functional significance for the tumour cell, but may still provide potential antigenic targets for immune cells. In addition, tumours can also express normal self proteins, but in abnormal quantities or locations (tumour-associated antigens). During T-cell development, T-cell precursors with a strongly self-reactive T-cell receptor are deleted in the thymus, resulting in a T-cell repertoire with a high affinity for foreign antigens and a weak affinity for self antigens.
Thus, tumour neoantigens being foreign induce strong immune response whereas tumour associated antigens are considered self and therefore induce weak immune response. CTL responses can be generated to weaker antigens, but require higher antigen concentrations and prolonged duration of exposure.
Challenges in Cancer Immunotherapy
Tumours are already engaging with the immune system in the patients with cancer. The goal of immunotherapy is to boost the immune response such that the balance shifts from tolerance to rejection. An immunotherapy may fail due to limiting factors at any point in the induction or effector phase. There may be inadequate quantity of tumour antigen present, or vaccination targeting shared, self-antigens may produce only weak T-cells responses that are insufficient to cause tumour regression.
It may also reflect the presence of a number of barriers to effective immunotherapy in established invasive tumours compared to premalignant lesions. The anti-tumour T-cells response may fail downstream of the induction phase because of:
(1) CTLs may remain in the periphery or in the draining lymph node without actually infiltrating the tumour site,
(2) CTLs may disseminate to the tumour but are unable to mediate anti-tumour activity,
(3) Activated T-cells may fail to continue expansion and maintain effector function,
(4) Activated T-cells may be switched off by immune suppressors secreted by tumours,
(5) Immune suppressive action of Regulatory T-cells on activated T-cells,
(6) tumours may alter their microenvironment to escape immune surveillance.
Combination Therapy for Cancer Treatment
Although multimodality therapy demonstrated a potential to cure early stage cancers, a key challenge for cancer therapy is to improve outcomes in the patients with advanced disease. Recently, the cancer chemotherapy is considered to synergise with immunotherapy although it often destroys the immune cells. Chemotherapy can have the immune stimulatory effects at number of points during immune response.
For example, causing lymphopenia it depletes regulatory T-cells as well as tolerised T-cells to tumour antigens. Homeostatic proliferation to restore immune cell numbers occurs following the cyclical chemotherapy. This phenomenon offers a window to skew the regenerating T-cells response back towards active anti-tumour activity.
In addition, chemotherapy induced apoptotic tumour cell death increases the quantity of antigen released and augments antigen cross-presentation by mature DCs to stimulate immune response. Chemotherapy can also sensitise tumour cells that cannot be directly lysed by treatment, to subsequent killing by immune cells.
Role of Adjuvant and Vaccine Delivery Systems
Newer generation of vaccines, particularly those based on recombinant proteins and DNA, will have a greater safety profile, but will be less immunogenic that attenuated organisms. An immne-adjuvant is an agent that can stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect of its own. Immuno-stimulatory adjuvants are predominantly derived from pathogens and often represent pathogen-associated molecular patterns, such as lipopolysaccharides and CpG nucleic acid motifs.
Adjuvants activate and engage components of the innate immune system to enhance T and B cell responses. Traditionally adjuvants have been used to increase the magnitude of an adaptive immune response to a vaccine.
However, recently adjuvants have been employed to guide the immune system to produce the most effective forms of immunity for each specific pathogen; for example T helper 1 (Th1) cell versus T helper 2 (Th2) cell, CD8+ versus CD4+ T cells, and specific antibody isotypes. Adjuvants are used in cancer immunotherapy to:
(1) increase the immune response to a weak tumour-antigen;
(2) facilitate the use of smaller doses of antigen; and
(3) permit immunization with fewer doses of vaccine. Very few vaccine adjuvants have been licensed for use in human.
Alum (aluminum salts) has been widely used for more than 70 years and until recently represented the only approved adjuvant in the United States. MF59 and AS03 (squalane oil in water emulsions) are licensed for adjuvanted influenza vaccines in Europe. AS04, a combination adjuvant composed of monophosphoryl lipid A (MPL) adsorbed to alum is approved for hepatitis B virus (HBV) and HPV vaccines in Europe and has been recently licensed in the USA.
Future Outlook for Cancer Vaccines
Tumour cell death can be immunogenic and that can be harnessed to improve cancer treatment outcomes. It may be possible to defeat the issues related to tumour antigen specificity by tailoring immunotherapies to individuals based on tumour gene expression profiles and human leukocyte antigen typing. However, this approach is likely to be both costly and time consuming.
A more readily adaptable strategy may be to manipulate the way tumour cells are killed and are sensed by immune cells such that tumour antigens are able to provoke tumour-specific cytotoxic T-cell responses. One can envision a situation in which chemotherapeutic agents are selected to kill tumour cells in a way that is immunogenic, or sensitize tumour cells to immune-mediated cell death. Further strategies may involve deletion of tumour induced immune-suppression to promote the anti-tumour immune response.
About the Author
Mansoor Amiji is a Distinguished Professor and Chairman of the Pharmaceutical Sciences Department in the School of Pharmacy, Bouve College of Health Sciences and Co-Director of the Nanomedicine Education and Research Consortium (NERC) at Northeastern University in Boston, MA.
Mayurkumar Kalariya is a doctoral candidate in the Department of Pharmaceutical Sciences at Northeastern University, Boston, MA and working as a Formulation Scientist at Alkermes Inc., Waltham, MA. He has received Dr. T.M.A. Pai Gold Medal and 36th Indian Pharmaceutical Congress Awards for academic excellence during the undergraduate program.
