• A BCG success story: From prevention of tuberculosis to optimal bladder cancer treatment

      Lamm, Donald L.; Morales, Alvaro; Department of Surgery, University of Arizona (Elsevier BV, 2021-08)
      BCG remains the most important vaccine for tuberculosis 100 years after its first use, and over the past 4 decades it has become the most widely accepted, effective drug used in the treatment of aggressive localized bladder cancer. This review chronicles the narrow path that led to approval and world-wide acceptance of BCG immunotherapy for bladder cancer while immunotherapy trials in other malignancies were abandoned. Six intravesical instillations of 5x10^8 CFU of BCG weekly after bladder tumor resection, first reported in 1976, is superior to resection alone and resection plus intravesical chemotherapy. Maintenance of effective immune stimulation is surprisingly difficult, but 3 weekly treatments 3, 6, and 12, 18, 24, 30 and 36 months after induction produces further significant reduction in tumor recurrence. This 3 week BCG maintenance schedule alone has reduced disease progression and mortality in multicenter randomized clinical trials. In the new age of immuno-oncology patients with many types of cancer now benefit from immunotherapy, but currently these modern agents are prohibitively expensive for most of the world. In contrast, the low cost and therefore low profitability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. Humanity has greatly benefited from early 20th century science that developed BCG and the benevolence of doctors Calmette and Guerin who put people over profit and widely shared cultures of the vaccine. The 21st century is bringing new immunotherapies and greatly expanding the types of malignancies that can be treated. Recombinant technology is expected to improve both the efficacy and production of BCG, hopefully expanding the availability of BCG and relieving the recurring supply shortage for both vaccination and cancer therapy.
    • Viable spores of Coccidioides posadasii Δcps1 are required for vaccination and provide long lasting immunity

      Shubitz, Lisa F.; Powell, Daniel A.; Trinh, Hien T.; Lewis, M. Lourdes; Orbach, Marc J.; Frelinger, Jeffrey A.; Galgiani, John N.; Univ Arizona, Valley Fever Ctr Excellence; Univ Arizona, Dept Immunobiol; Univ Arizona, Sch Plant Sci; et al. (ELSEVIER SCI LTD, 2018)
      Coccidioidomycosis is a systemic fungal infection for which a vaccine has been sought for over fifty years. The avirulent Coccidioides posadasii strain, Delta cps1 which is missing a 6 kb gene, showed significant protection in mice. These studies explore conditions of protection in mice and elucidate the immune response. Mice were vaccinated with different doses and viability states of Delta cps1 spores, challenged with virulent C posadasii, and sacrificed at various endpoints, dependent on experimental objectives. Tissues from vaccinated mice were harvested for in vitro elucidation of immune response. Vaccination with viable Delta cps1 spores was required for protection from lethal challenge. Viable spore vaccination produced durable immunity, lasting at least 6 months, and prolonged survival (>= 6 months). The C. posadasii vaccine strain also protected mice against C immitis (survival >= 6 months). Cytokines from infected lungs of vaccinated mice in the first four days after Cp challenge showed significant increases of IFN-gamma, as did stimulated CD4(+) spleen cells from vaccinated mice. Transfer of CD4(+) cells, but not CD8(+) or B cells, reduced fungal burdens following challenge. IFN-gamma from CD4(+) cells in vaccinated mice indicates a Th1 response, which is critical for host control of coccidioidomycosis. (C) 2018 Elsevier Ltd. All rights reserved.