“Attack!” Cellular Therapies to Attack Pathogens and Tumors

Allogeneic hematopoietic stem cell transplantation (HSCT) was the first cellular immunotherapy to arise and, due to its overwhelming success, it remains a mainstay in the treatment of refractory leukemias and lymphomas [1]. More than 16,000 allogeneic transplantations per year are performed in Europe alone, most of them for refractory myeloid and lymphoid neoplasias [1]. Even though the primary goal of HSCT was “organ replacement” of a diseased by a healthy hematopoietic system, its pioneers very early on recognized the ability of the graft to eradicate residual blasts [2‒5]. The antileukemic activity, however, came at a price: at the time termed “secondary disease,” now known as graft-versus-host disease (GvHD), which the first generation of transplanters surmised were both immune-mediated reactions of grafted cells with host, and which they equally surmised were birds of a feather [3, 6]. Both hypotheses turned out to be true [7‒9]. To this day, despite a greater armamentarium of immunosuppressive medications and a better understanding of histocompatibility, HSCT remains a walk on the edge between GvHD from too much and relapse from too little activity of the grafted T cells [10].

From this conflict, the first more exclusive cellular immunotherapy, donor lymphocyte infusion, arose, which harbors the same risk of GvHD as unmodified stem cell grafts, but was, with carefully escalating dosing, shown to be exquisitely effective in chronic myeloid leukemia [11, 12], the most prevalent indication for allogeneic transplantation before the advent of the BCR-ABL kinase inhibitors [13]. The risk of GvHD development from allogeneic lymphocyte transfer has fueled, and continues to fuel, the quest for ever more specific cellular immunotherapies, either by selecting desired T-cell specificities from allogeneic T-cell products, educating T cells to lose alloreactivity, depleting alloreactive T cells to enrich memory cells, or by endowing autologous T cells with the ability to specifically recognize desired antigens, predominantly by transfer of artificial genes encoding specific chimeric antigen receptors (CARs) or T-cell receptors [14‒31].

This collection of articles authored by experts in the field of cellular immunotherapy provides examples of such highly innovative and promising therapies. The articles deal with innovative cell therapies that are already regularly used in the clinics; others provide glimpses into the near future, identifying areas of unmet medical need and possible avenues toward their resolution. As any such article collection must be, it is far from complete in representing the full breadth of available and potential future cellular immunotherapies, nor weighted in terms of the respective magnitude of the individual therapy’s roles in current clinical practice. Suffice it to say, cellular immunotherapy, both with primary and genetically modified T cells, is here, with only more to come. Or is it?

If the editors of Transfusion Medicine and Hemotherapy were not fascinated by the emerging field of cellular immunotherapy and wanted to share their fascination with the readership, this special collection of articles would not have been proposed. And yet this article collection comes with a black box warning: The production of cell therapeutics is (i) almost always customized and personalized, (ii) more hand-crafted than factory-produced, and (iii) inherently more expensive by several orders of magnitude than any other form of therapy developed to date, including in vivo gene therapeutics.

The systemic application and potentially life-long persistence of genetically modified cells require careful quality control of each individual product, using assays that not just quantify the active substance but also allow predictions about its fate in vivo. Cell therapy manufacturing and testing essentially follows the same regulatory framework as the manufacturing of conventional drugs, whether they are small molecules or biologicals, except that in most cases each dose constitutes a batch of the highly personalized cellular medicinal product, hugely inflating the quality control effort per individual dose.

The financial toxicity of cellular immunotherapies is undeniable, and “cell engineers” are aware of all these challenges. The currently centrally approved cellular immunotherapies cost between 200,000 and 400,000 euros. Trials are ongoing that seek to extend approved cellular therapies to currently not eligible patient groups (e.g., CD19-CAR-T cells for elderly patients), and to diseases that are orders of magnitude more common (e.g., CD19-CAR-T cells for autoimmune disease) [32‒34]. Unfortunately, some approved cellular immunotherapies no longer promise the coveted cures, but at best only moderately long remissions or a bridge to transplantation [31, 35, 36] and infectious complications after CAR-T-cell therapy are frequent [37]. Recently, the Federal Joint Committee (Gemeinsamer Bundesausschuss [G-BA]) withdrew the temporary coverage for a CAR-T-cell immunotherapy for multiple myeloma, namely, Abecma (www.g-ba.de/bewertungsverfahren/nutzenbewertung/1068/#nutzenbewertung). Negotiations on reimbursement for cellular immunotherapies sometimes fail because price expectations of the pharmaceutical manufacturers and evaluation of the therapy by health technology experts appear to be irreconcilable.

Nevertheless, cellular therapies are at the forefront of research and the development of new therapeutic approaches is in full swing. The use of unmanipulated [15, 16, 38‒41] and genetically modified T cells [26‒31], natural killer [42‒44], and cytokine-induced killer cells [45] has been shown to be effective against infections and various cancers. In order to make allogeneic cells more suitable and obtain maximally standardized products, lymphocytes are increasingly being generated from in vitro induced pluripotent stem cells or enriched from umbilical cord blood and off-the-shelf therapies are under development [46‒51]. However, challenges remain to be addressed, as phenotype and effector functions of the in vitro generated cells are distinct from those of peripheral blood-derived primary cells currently used in the clinic. CAR-T-cell therapy has achieved outstanding clinical success in hematology with CD19-specific CAR-T cells against B-cell leukemias and lymphomas and B-cell maturation antigen-specific CAR-T cells for the treatment of multiple myeloma, significantly improving patient survival [31, 37]. Due to other challenges, clinical experience with CAR-T therapy in oncology remains limited. These challenges include limited efficacy, antigen escape, low persistence of effector cells, poor enrichment and tumor infiltration, the immunosuppressive microenvironment, and the risk of secondary malignancies. These aspects must be considered disease- and context-specific when developing these therapies.

Additionally, a lot of work is also being done on optimizing the binding between receptors and target. Indirect CAR technologies including universal adapter CARs and “on-off” switchable CARs may be the future of CAR therapies [52‒56]. These CARs expand recognition beyond the well-known targets CD19 and B-cell maturation antigen and may provide a simple solution to the complex challenge of antigen heterogeneity, especially in the treatment of solid tumors. Recently, it was also shown that regulating the single chain variable fragment affinity directly regulates CAR-T-cell activity [57]. Therefore, switching modules, which usually function under physiological conditions, can increase the affinity and also the specificity of cellular products. The affinity changes are reversible and the switching can be repeatedly induced.

“Cell Engineers” are aware of these challenges, and there are increasing efforts to produce cellular drugs at specialized academic institutions by creating new and improving available technologies, thus counteracting de-commercialization [58, 59]. Tools that make the generation of genetically modified effector cells cost-efficient, highly reproducible, and scalable will revolutionize cellular therapies for severely affected patients and will thereby open up new areas. New flexible concepts will be required in the era of patient-specific therapies to make the dream of accessibility for a large patient collective in a reasonable time frame come true.