A tale of the monoclonal anti-CD20 antibodies, in tribute to prof. Waclaw Szybalski (1921-2020).

Technical advances that lead to the era of targeted therapeutics demanded several milestones that were reached in the second half of the previous century. Professor Waclaw Szybalski was the first one to perform a stable gene transfer in eukaryotic cells. To do so, he used his own designed system consisting of HPRT-deficient cells and HAT selective medium. Moreover, the first-ever hybridoma cells were also constructed by Waclaw Szybalski's team. These spectacular achievements made him not only a forerunner of gene therapy, but also became a foundation for immunotherapy, as hybridoma and their selection by the HPRT-HAT system turned into a crucial technical step during production of monoclonal antibodies (mAbs). Herein, we present a story of anti-CD20 mAbs, one of the most successful lines of anticancer drugs. When looking back into history, the prototypic mAb rituximab was considered the biggest step forward in the therapy of B-cell malignancies. Nowadays, the second and third generations of anti-CD20 mAbs are approved in clinical use and numerous breakthrough studies on immune effector mechanisms were conducted with the aforementioned immunotherapeutics as a model.

Historique de l'immunothérapie. Changement de paradigme ?

HISTORY OF IMMUNOTHERAPY. PARADIGM CHANGE?: Born at the dawn of the 20th century with W.B. Coley's intratumoral injections of bacteria, cancer immunotherapy was built on the corpus of the immune surveillance theory in 1957, modified by R.D. Schreiber in 2004. Scientific knowledge and technological advances have allowed it to become efficacious and to expand in the 21st century as the 4th and most important pillar of cancer treatment.

Managing the future: the Special Virus Leukemia Program and the acceleration of biomedical research.

After the end of the Second World War, cancer virus research experienced a remarkable revival, culminating in the creation in 1964 of the United States National Cancer Institute's Special Virus Leukemia Program (SVLP), an ambitious program of directed biomedical research to accelerate the development of a leukemia vaccine. Studies of cancer viruses soon became the second most highly funded area of research at the Institute, and by far the most generously funded area of biological research. Remarkably, this vast infrastructure for cancer vaccine production came into being before a human leukemia virus was shown to exist. The origins of the SVLP were rooted in as much as shifts in American society as laboratory science. The revival of cancer virus studies was a function of the success advocates and administrators achieved in associating cancer viruses with campaigns against childhood diseases such as polio and leukemia. To address the urgency borne of this new association, the SVLP's architects sought to lessen the power of peer review in favor of centralized Cold War management methods, fashioning viruses as "administrative objects" in order to accelerate the tempo of biomedical research and discovery.

Population mixing for leukaemia, lymphoma and CNS tumours in teenagers and young adults in England, 1996-2005.

BACKGROUND: Little aetiological epidemiological research has been undertaken for major cancers occurring in teenagers and young adults (TYA). Population mixing, as a possible proxy for infectious exposure, has been well researched for childhood malignancies. We aimed to investigate effects of population mixing in this older age group using an English national cancer dataset. METHODS: Cases of leukaemia, lymphoma and central nervous system (CNS) tumours amongst 15-24 year olds in England (diagnosed 1996-2005) were included in the study. Data were obtained by ward of diagnosis and linked to 1991 census variables including population mixing (Shannon index); data on person-weighted population density and deprivation (Townsend score) were also used and considered as explanatory variables. Associations between TYA cancer incidence and census variables were investigated using negative binomial regression, and results presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). RESULTS: A total of 6251 cases of leukaemia (21%), lymphoma (49%) and CNS tumours (30%) were analysed. Higher levels of population mixing were associated with a significant decrease in the incidence of CNS tumours (IRR=0.83, 95% CI=0.75-0.91), accounted for by astrocytomas and 'other CNS tumours'; however, there was no association with leukaemia or lymphoma. Incidence of CNS tumours and lymphoma was 3% lower in more deprived areas (IRR=0.97, 95% CI=0.96-0.99 and IRR=0.97, 95% CI=.96-0.98 respectively). Population density was not associated with the incidence of leukaemia, lymphoma or CNS tumours. CONCLUSIONS: Our results suggest a possible role for environmental risk factors with population correlates in the aetiology of CNS tumours amongst TYAs. Unlike studies of childhood cancer, associations between population mixing and the incidence of leukaemia and lymphoma were not observed.

Ludwik Gross, Sarah Stewart, and the 1950s discoveries of Gross murine leukemia virus and polyoma virus.

The Polish-American scientist Ludwik Gross made two important discoveries in the early 1950s. He showed that two viruses - murine leukemia virus and parotid tumor virus - could cause cancer when they were injected into susceptible animals. At first, Gross's discoveries were greeted with skepticism: it seemed implausible that viruses could cause a disease as complex as cancer. Inspired by Gross's initial experiments, similar results were obtained by Sarah Stewart and Bernice Eddy who later renamed the parotid tumor virus SE polyoma virus after finding it could cause many different types of tumors in mice, hamsters, and rats. Eventually the "SE" was dropped and virologists adopted the name "polyoma virus." After Gross's work was published, additional viruses capable of causing solid tumors or blood-borne tumors in mice were described by Arnold Graffi, Charlotte Friend, John Moloney and others. By 1961, sufficient data had been accumulated for Gross to confidently publish an extensive monograph--Oncogenic Viruses--the first history of tumor virology, which became a standard reference work and marked the emergence of tumor virology as a distinct, legitimate field of study.

The leukemias: a half-century of discovery.

Studies of the leukemias in the laboratory and in the clinic have generated many new concepts and therapies that will undoubtedly continue to be rapidly applied to the other forms of systemic cancer, particularly the concept of narrowly targeted personalized therapy that has proven so effective in CML. It seems likely that other subtypes of leukemia will eventually approach the success achieved with APL, CML, and pediatric ALL.

The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment.

Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia.