Self-defense of human sarcoma cells against cytolytic lymphoid cells of their host.

Metastatic human sarcomas temporarily respond to radio-chemotherapy relapse and remain highly resistant to further combination chemotherapy as to a curative effect, including checkpoint control.

[Erratum] Virological and immunological connotations of apoptotic and anti-apoptotic forces in neoplasia.

The authors would like to acknowledge that the Coriphosphine O stain shown in the upper panel of Figure 8 was a kind gift from Dr T.P. Loughran of the H.L. Moffitt Cancer Center, Tampa, FL, USA. [the original article was published in the International Journal of Oncology 19: 473-488, 2001; DOI: 10.3892/ijo.19.3.473].

Discordant biological and toxicological species responses to TLR3 activation.

Toll-like receptors (TLRs) are highly conserved type 1 membrane proteins that initiate a multiplicity of transient gene transcriptions, resulting in innate and adaptive immune responses. These essential immune responses are triggered by common TLR pattern recognition receptors of microbial products expressed through the cytoplasmic carboxy-terminal Toll/IL-1 domain. Toll/IL-1 adapter protein cascades are induced by an activated Toll/IL-1 to induce transient transcription responses. All TLRs, with the exception of TLR3, use an MyD88 adapter to Toll/IL-1 to initiate a proinflammatory cascade. TLR3 uses the toll receptor 3/4 induction factor adapter to initiate a different cytosolic adapter cascade with double-stranded RNA agonists. This non-MyD88 pathway induces both NF-κB and type 1 interferon responses. By using a TLR3-restricted double-stranded RNA agonist, rintatolimod, we demonstrate significant unexpected differences in toxic responses between rats and primates. The mechanism of this differential response is consistent with a relative down-regulation of the NF-κB inflammatory cytokine induction pathway in the cynomolgus monkey and humans, but not observed systemically in rat. Our findings suggest evaluation of TLR3 agonists in drug therapy.

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers.

Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.

Evidence accumulating in support of cancer vaccines combined with chemotherapy: a pragmatic review of past and present efforts.

In the early 1970s supervised clinical trials were initiated at The University of Texas M.D. Anderson Hospital in Houston, TX, for the combination of viral oncolysate-based vaccines and contemporary chemotherapy for the treatment of patients with metastatic melanoma and sarcomas. This therapeutic approach was then generally considered to be inappropriate based on a widely held belief that the efficacy of cancer vaccines would be negated by the immunosuppressive effects of the chemotherapy. Not NCI grants, but institutional funds supported these clinical trials. These early clinical trials included in vitro tests for anti-tumor cell antibodies and cytotoxic lymphocytes both in autologous and allogeneic settings and showed that these faculties remained active even after chemotherapy. The contemporary reports of unexpectedly favorable clinical results are recited in this article. Despite these most promising results, support from federal granting agencies (the NIH/NCI) was repeatedly denied; these denials were based on the prevailing dogma that the two treatment modalities are expected to be antagonistic and not synergistic or not even additive. However, thirty years later, now in the new era of molecular medicine, a rapidly increasing number of peer-reviewed publications appear and offer convincing evidence that strongly substantiate the therapeutic value of combined cancer chemoimmunotherapy. The important provision is that the sequencing and dosing of the two major treatment modalities, the vaccination and the chemotherapy, are to be pre-tested and then the methodology is to be adhered to in the new clinical trials. New sophisticated experiments carried out in vitro and in vivo and subsequent clinical trials attest to the potential value of this combinatory approach and explain the underlying molecular mechanisms. This pragmatic review recapitulates the empirically administered earliest clinical trials, and lists and interprets, in view of their molecular immunomodulatory effects, the exemplary new clinical trials.

Human natural killer cells: a comprehensive review.

The senior author of this comprehensive review observed and reported in 1969 that his lymphocytes killed allogeneic tumor cells in vitro. Some of his research associates and technicians and other healthy individuals also yielded such killer lymphocytes. The team considered pre-immunization to cancer occurring in individuals after in-family or professional exposure to patients with cancer (in an era when the concept of viral etiology of cancer was receiving major support); or that lymphocytes can acquire through blastic transformation immune reactivity to allogeneic cells anew in vitro. The phenomenon was eventually referred to as 'lymphocytes practicing Burnet's immunosurveillance.' Project site visitors of the USA NCI first viewed these observations as a matter of 'in vitro artifacts' being in opposition to strong tumor- specific cytotoxicity of tumor-bearing patients' lymphocytes recognized in the vast majority of other assays. After NCI funds were released for intramural studies on the phenomenon of non-specific cytotoxicity by lymphocytes, recipients (other than the senior author) of these NCI funds later characterized (1973-1975) the 'indiscriminately' cytotoxic lymphocyte populations as those of 'natural killer (NK) cells.' In this article, the original observations made in 1969-1971 are reviewed based on genuine material preserved by the senior author and are explained in view of recent discoveries that were not available at the time of the original observations. NK cells display a fascinating history arising first in urochordates during the cambrian explosion. At that level, NK cells protected their hosts from incompatible cell colony fusions and against intracellular, especially viral, pathogens. Since then, viruses evolved evasive maneuvers to escape NK cell attack on the infected cells. NK cells persisted after the evolution of adaptive immunity in cartilaginous fish fitting seamlessly into the new system. In mammals, NK cells assumed the role of chief arbitrators between the fetal trophoblast and maternal immune reactions to the semi-allograft fetus. Tumors induce in NK cells the same (inactivating; mediating Th2-type immunity) reactions the fetal trophoblast engenders in utero, but NK cells may overcome the host's tolerance to its tumor and kill tumor cells, especially when converted into lymphokine-activated killer (LAK) cells by molecular mediators of Th1-type immunity. The authors prepare and utilize LAK cells and IL-2 for adoptive immunotherapy of patients with metastatic melanoma and kidney carcinoma. A patient with malignant ascites due to ovarian carcinoma entered remission on LAK cell therapy. Just as dendritic cells, the major antigen presentors, may undergo malignant transformation, NK cells are also subject to transformation into FasL-producer virulent lymphoma-leukemia cells. The senior author reported in 1970 a patient with 'lymphosarcoma cell leukemia' whose circulating lymphoma cells killed indiscriminately human sarcoma and carcinoma cells. The exemplary case history of another patient with NK cell lymphoma-leukemia treated by the authors is presented.