Recent successes of cancer immunotherapy: a new dimension in personalized medicine?

Abstract

Until recently, cancer therapy was limited to "debulking approaches" including surgery, chemo-radio-and hormono-therapy and compounds targeting oncogenes or proangiogenic pathways. Unfortunately, phase III studies pointed out that such strategies, remarkable against primary tumors, mostly affected time to progression but rarely overall survival, suggesting that long-term protective effects were not achieved. Immunotherapy which has long been opposed to chemotherapy because of its susceptibility to drug-induced apoptosis and its lack of efficacy to immediately "debulk," comes of age for a main reason: immunotherapy may be the sole approach to elicit cancer-specific adaptive immune responses and long-term protection against metastases. Can it be any cure without the involvement of the immune system? Cancer immunotherapy currently involves several complementary strategies: immune cell transfer, vaccines, cytokines, vaccine adjuvants, and monoclonal antibodies (mAb) endowed with antibody-dependent cell cytotoxicity or interfering with immune checkpoints. Several of these approaches are reviewed in this issue of Targeted Oncology.Important clinical benefits were first demonstrated using adoptive transfer of autologous tumor-infiltrating lymphocytes resulting in objective cancer regression in a significant proportion of patients with metastatic melanoma. In particular, the combination of cell transfer with a lymphodepleting regimen induced complete durable responses in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current cell transfer therapy approaches using autologous cells genetically engineered to express conventional or chimeric T cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma, and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans and has evolved towards the administration of "young TILs" [1,2].Recently, the US Food and Drug Administration approved two novel immunotherapy agents, one based on a cancer vaccine (Sipuleucel-T, Dendreon) in patients with indolent hormone refractory prostate cancer and the other one based on targeting a pivotal T cell inhibitory receptor (anti-CTLA4 mAb, ipilimumab/Yervoy, BMS) in metastatic melanoma patients, which provide a survival benefit in two phase III clinical trials [3,4].These encouraging clinical results will be followed by many expected breakthroughs, according to the current evaluations worldwide. These include:1. Therapeutic vaccines capable of inducing robust T cell responses, using long overlapping peptides or recombinant poxviruses or synthetic mRNA [5][6][7]. 2. Different classes of immune adjuvants such as Toll-likereceptor agonists currently under clinical trial in [8].

CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging

“…The immunogenicity of cell death can significantly influence subsequent antitumor immune response and the overall efficacy of a drug. [21][22][23] Specifically, it has been suggested that the translocation of the endoplasmic reticulum resident calreticulin-ERp57 complex to the plasma membrane is useful for immunogenic cell death. 24 Subsequently, it was shown that the nuclear alarmin HMGB1 has to be released into the tumor microenvironment to engage TLR4 on host DCs to facilitate antigen processing and presentation.…”

Improving lung cancer survival; time to move on

“…Evidence that the immune system of the host can influence cancer incidence, cancer growth, response to therapy, and the prognosis of the disease, is growing [18]. Therefore it was thought that conventional therapy combined with immunotherapy based on a pretreatment profile of the immune system of the host could be a valuable tool to increase the survival of early stage NSCLC [19].…”

Molecular Mimics of the Tumour Antigen MUC1

“…Several complementary treatment regimes such as immune cell transfer (adoptive immunotherapy), tumour vaccines, cytokine therapy, and monoclonal antibodies targeting immune response checkpoints [1]–[3] may form part of this therapy. One form of adoptive immunotherapy for cancer patients involves loading tumour-associated antigens (TAAs) in vitro onto macrocytic dendritic cell (DCs) precursors isolated from the patient.…”