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Cancer vaccine types and delivery systems (part Two)

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3 Cancer vaccine adjuvant selection

The initial aim of formulating vaccines in adjuvants was to deliver the antigen in a poorly metabolizing and slowly degrading substance. The intention was to favor the slow and sustained release of the antigen to be captured by antigen-presenting cells (APCs) and be subsequently presented to T cells. Aluminum salts are widely used to favor T helper cell 2 (Th2)-mediated humoral immunity, but they are less efficient for promoting Th1-dependent immunity. To this aim, water-in-oil adjuvants have been developed to create a depot of the antigen at the site of the injection. The next generation of vaccine delivery agents includes nanoparticles such as silica or liposomes or synthetic polymers, which are ideal vehicles to be taken up by dendritic cells (DCs) patrolling within the subcutaneous tissues. However, the challenge with such supports is to selectively promote DC uptake while eluding the systemic reticuloendothelial network of macrophages, which routinely clear circulating particles. In addition to these substances designed to favor delivery of the antigen to APCs, today’s therapeutic vaccines also contain another class of adjuvants aimed to deliver danger signals to activate the immune system, as antigen alone may fail to prime effective T cell responses or even induce tolerance.

4 The choice of cancer vaccine delivery system

The choice of delivery systems and route of immunization depends on the end use of the vaccine. For practical reasons and minimal side effects, most prophylactic vaccines are administered via the skin, usually by subcutaneous injections in the epidermis or the dermis. These two locations are ideal, as they are enriched respectively in Langerhans DCs and dermal DCs, both cell populations being very efficient in capturing and processing antigens. The oral route is also very convenient and is used by vaccines against polio, typhoid fever, cholera, and rotavirus. The oral route is, however, more challenging in view of the extreme conditions in the gastrointestinal tract, including the low pH in the stomach and the presence of microbiota, which may degrade the antigen before it reaches the lymphoid organs. Moreover, the usually tolerogenic gut environment may not be ideal to generate a strong systemic immune response.

With regard to therapeutic vaccines used to treat chronic noncontagious diseases such as cancer, atopy, or diabetes, both immediate cellular effector responses and long-term immunity are desired to guarantee the continuous immune-surveillance of the disease. Although prophylactic vaccines for global immunization programs must be simple, inexpensive, and given via a noninvasive route, therapeutic cancer vaccines can benefit from more complicated technologies and use more invasive routes of delivery if beneficial for the patient. There is a very large array of cancer vaccines under development which use various delivery systems, and which are being tested in clinical trials. Other delivery routes tested in therapeutic cancer vaccines range from subcutaneous and intradermal to more invasive intraperitoneal and intranodal injections, to optimize antigen uptake by APCs and favor a local potent immune response. For instance, particulate therapeutic vaccines such as virosomes or nanoparticles can be injected in LNs using an ultrasound-guided imaging procedure. Although most of these strategies are still in the development stage, the potential to achieve strong and long-lasting antitumor responses is high, owing to new delivery systems and better understanding of T cell memory development.

Reference

[1] FUTURE II Study Group. Quadrivalent vaccine against HumanPapillomavirns to prevent high-grade cervical lessions. N Engl J Med, 2007, 356(19): 1915

[2] Olsson SE, Villa LL, Costa RLR, et a1. Induction of inmmne memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/1 1/16/18 LI virus-like particle (VLP) vaccine. Vaccine, 2007 (25): 4931

[3] Harris JE, Ryan L, Hoover Jr HC, et a1. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Orwol, 2000, 18(1): 148

[4] Berd D, Maguire Jr HC, Mastrangelo MJ, et a1. Treatment of human melanoma with a hapten — modified antologous vaccine. Ann NY Acad Sci, 1993, 690(8): 7

[5] Remann R, Goldschmidt AJ, Richter A. Adjuvant therapy of renal cell carcinoma patients with an autologous tumor cell lysate vaccine: a-year—follow—up analysis AnticancerRes, 2003, 23(2A): 969

[6] Mitchell MS, Kan — Mitchell J, Kempf RA, et a1. Active specific im-munotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res, 1988, 48(20): 5883


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