The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3ITD AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG1 prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3ITD AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.

No abstract

ZusammenfassungDie chimäre Antigenrezeptortherapie (CAR-Therapie) entwickelte sich zu einem der vielversprechendsten immunonkologischen Therapieansätze für die Behandlung von Krebs. Aufgrund der klinischen Erfolge wurden bisher 2 CD19-spezifische CAR-T-Zell-Therapien in den USA und der EU zugelassen. Die bahnbrechenden Ergebnisse weckten sowohl in der Industrie als auch in der Forschung großes Interesse und sorgten für eine rasante Entwicklung in diesem Feld.

There are currently around 550 active clinical trials utilizing CAR T cells. The industry is growing by as much as 37.5%, according to recent reports, and in terms of investment, almost $975 million has been spent. Two therapies are now approved, with more set to follow. Almost half of all clinical trials that were initiated in 2019 have a sponsor or involve collaborations, illustrating the importance of collaboration to this field: industry, academia and small biotechnology companies all have a role to play. But even as this dynamic field sees such promising growth and investment, questions remain over what the future of cell therapy manufacture will look like. There are emerging trends which provide clues-for example, the increasing use of allogeneic cell sources as off-the-shelf drugs are developed. This is being seen not only in CAR T cells but also in natural killer (NK) cells and even in macrophages. Switch receptors and control receptors are also areas seeing further development, and CARs are being developed that secrete a range of cytokines and enzymes, enabling them to migrate to different locations within tissues and tumors. Combination therapies may also prove to be key to the further success of the field. However, cell therapies differ greatly from small molecules and other drugs, and the way they are manufactured is complex and involves a variety of steps. Especially when using manual manufacturing systems, a lot of risk is introduced. This increases cost, as skilled staff and stringent manufacturing conditions are required. Concerns over manufacturing challenges associated with cell therapies, such as product shortages/delays that could threaten growth and directly impact the length of time to market, are growing within the industry. In this roundtable, six cell manufacture experts discuss the progress towards standardized and fully automated generation of gene modified CART and CAR NK cells-and address the remaining obstacles.