Challenges in Adoptive T Cell Therapy for AML

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Erden Atilla	--	6115	2023-05-24 08:09:39	\|
2	summary	Erden Atilla	-3156 word(s)	2959	2023-05-26 15:23:00	\| \|
3	format layout	Fanny Huang	Meta information modification	2959	2023-05-29 06:04:02	\| \|
4	references update	Fanny Huang	-3 word(s)	2956	2023-05-29 07:20:50	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15102713

Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed-refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything, considering only around 30% of patients show a response but with consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. Below information first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML.

acute myeloid leukemia cellular therapies chimeric antigen T cells

1. Introduction

Since the early studies in the eighteenth century on the development of the first vaccines, researchers have attempted to eliminate tumors by harnessing the immune system. One strategy, adoptive cell therapy, uses T cells that can recognize tumor antigens through tumor-specific receptors. Since the 1980s, chimeric antigen receptor T cells (CAR T cells) have revolutionized the treatment algorithms of patients with lymphoma, acute lymphoblastic leukemia, and multiple myeloma ^[1]. They have shown dramatic success in the clinic, improving survival and quality of life for patients that would otherwise reach the end of care with conventional therapies. Currently, six CAR T cell products are approved by the United States Food and Drug Administration (FDA), and approvals are expanding to Europe and many other countries around the world.

There are distinct considerations in acute myeloid leukemia (AML), the most common acute leukemia in adults. AML is an aggressive blood cancer characterized by a collection of immature cells of myeloid lineage that exhibit partial or complete arrest of maturation ^[2]. The heterogeneity and intrinsic variability of the tumor make patient responses hard to predict, and around 75% of patients ultimately relapse. Treatment resistance (10–40%) and relapse remain the major consequences during disease follow-up, highlighting the urgent need for novel therapeutic approaches ^[3]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option, but many patients are not suitable candidates ^[4].

Many in vitro and in vivo studies have shown that CAR T cells against surface proteins, such as CD33, CD123, CLL-1, CD13, CD7, NKG2D ligand, CD38, CD70, and TIM3, effectively eradicate AML cells ^[5]. However, the clinical trials are limited, with not very promising response rates accompanied by high ‘on-target off-tumor’ toxicity due to the frequent expression on healthy hematopoietic stem cells or progenitors, as well as other tissues.

2. Challenges in Adoptive T Cell Therapy for Acute Myeloid Leukemia

2.1. AML Is Highly Heterogenous

Normal hematopoietic stem cells give rise to mature cells of the myeloid, lymphoid, and erythroid/megakaryocyte lineages. Single-cell RNA sequencing (scRNA-seq) analyses have shown that normal hematopoietic stem cell (HSC) commitment proceeds through a series of increasingly lineage-committed progenitor states ^[6]. AML consists of leukemia stem cells (LSCs) and differentiated cells. LSCs sustain the disease and display self-renewal, quiescence, and therapy resistance. Differentiated AML cells that lack stem cell characteristics affect tumor biology through pathologic effects on the tumor microenvironment ^[7].

AML is a highly heterogeneous disease between patients due to the presence of specific chromosomal abnormalities, gene mutations, or gene fusions. Epigenetic modifications such as histone modifications, DNA methylation, and post-transcriptional regulation of mRNAs by noncoding RNAs have additional roles in the pathogenic heterogeneity ^[8].Furthermore, a crucial problem in patients with relapse or treatment resistance is intratumoral heterogeneity, formed with different subclones of leukemia cells, with distinct genetic and epigenetic features coexisting within a single patient ^[9]^[10]. Highly heterogeneous LSCs have variable drug sensitivity. Some LSCs acquire quiescence, which plays a major role in drug resistance profiles ^[11]^[12]. Recent advances in genomic, transcriptomic, epigenomic, and proteomic data have helped to elucidate the biological differences between pre-treatment AML cells and their equivalents in relapse.

2.2. There Is No Ideal Surface Antigen to Target

CAR T cells can bind to cell surface molecules without requiring any antigen processing or HLA expression ^[13]. The choice of which surface antigen to target is the critical step in manufacturing. The most important feature of an ideal target is the unique and high expression profile on tumor cells, above the detection and activation threshold for CAR T cells, as well as tolerable or no expression on healthy tissues to prevent toxicity. CD19 is now a widely accepted B lineage target of lymphoma and leukemia that is expressed in all tumor cells and absent in normal HSCs as well as all normal tissues ^[14]. Despite many discoveries related to the immunopathology of AML, a single AML-specific target has still remained elusive.

2.3. Interactions in the Tumor Microenvironment

LSCs reside in a specialized niche that promotes their survival and chemoresistance, through which they can alter their microenvironment ^[15]. LSCs secrete pro-angiogenic VEGF and interleukins to stimulate angiogenesis to provide additional nutrients, oxygen, and growth factors and to promote proliferation ^[16]^[17]. AML blasts support a low-arginine microenvironment ^[18]. AML LSCs induce the expression of a growth-arresting protein, GAS6, in BM stromal cells ^[19]. AML cells promote the expression of immunomodulatory factors that impair cytotoxic T lymphocyte (CTL) activation in the tumor microenvironment ^[20]; these factors include programmed death receptor (PD-1), transforming growth factor β (TGF β), arginase II, prostaglandin E2 (PGE2), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG3), and T cell immunoglobulin and mucin-containing-3 (TIM3) on T cells ^[21]. Furthermore, leukemia cells modulate the NK cell receptor repertoire that inhibits NK cell activity ^[22]. The interactions are reciprocal: the niche cells also foster LSC growth. Assessment by scRNA-seq, the cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), or single-cell assay for transposase-accessible chromatin (ATAC) sequencing has paved the way for the study of cellular heterogeneity and intercellular hierarchies and for the obtaining of insights into the cellular ecosystem of malignant and normal cells.

3. Promising Strategies to Overcome Challenges

3.1. Safer Targets with Less ‘On-Target Off-Tumor’ Effect

Some potential targets appear more reliable in terms of off-tumor toxicity, especially on normal hematopoietic cells, but none of them have proven to be an ideal target in AML. C-type lectin like molecule-1 (CLL-1) is a type II transmembrane glycoprotein overexpressed in over 90% of AML patients on AML blasts, LSCs and differentiated myeloid cells absent in normal CD34+CD38- hematopoietic stem cells. CD70, a ligand for CD27 identified as a type II transmembrane glycoprotein, was reported to be expressed on AML bulk cells and leukemic stem cells but not on normal hematopoietic stem cells. It showed promising anti-tumor effect without toxicity on healthy HSCs ^[23]. Efforts to discover efficient targets for immunotherapeutic strategies accelerated following technical progress in proteomic and transcriptomic assays. These assays help to understand cellular behavior on the protein level instead of immunophenotyping malignant cells. Hoffman et al described mass-spectrometry based phenotyping of HL60 and NB4 cell lines ^[24]. Perna et al performed surface-specific proteomic and transcriptomic studies in AML patients and normal tissues to indicate a potential therapeutic target. However, none of the surface proteins showed a similar expression profile to CD19. These studies suggested a combinatorial targeting strategy, which is discussed further in other sections ^[25]. Kohnke and colleagues aimed to discover de novo targets using cell-surface capture technology to detect the surfaceome, a set of proteins expressed on the surface of primary AML patient samples, including surface receptor, transporters, adhesion molecules among others. They identified three promising targets: CD148, ITGA4 and Integrin beta-7. Among these, Integrin beta-7 was the most favorable due to low or absent expression in healthy hematopoietic tissues ^[26]. In a recent scRNA-sec approach, two antigen targets-CSF1R and CD86 revealed potential targets for CAR T-cell therapy with broad expression on AML blasts accompanied by minimal toxicities toward relevant healthy cells and tissues ^[27].

3.2. Limiting the ‘On Target-Off Tumor’ Effect

Unacceptably severe or prolonged toxicities, especially cytopenias and infections, can occur more frequently than in clinical trials with CD19 CAR T cells in lymphomas due to older and therapy-resistant patient populations. It is crucial to maintain anti-cancer immune surveillance and clinical efficacy while avoiding toxicity. Safety or suicide genes are widely used to alleviate toxicity from CAR T cells ^[28]^[29]^[30]. Alternatively, administration of cross-reactive CAR T cells can be a bridge to allogeneic stem cell transplants. Tasian et al showed three different approaches (anti-CD123 messenger RNA electroporated CAR T cells, administration of alemtuzumab, and administration of rituximab to CD20-coexpressing CART123) to eliminate CD123 CAR T cells without effecting the antitumor activity in murine models ^[31].

Many cell engineering approaches have attempted to improve safety in designing CARs, such as logic gating of T cell recognition and SnyNotch receptors ^[32]. Mutation in the anti-CD123 CAR antigen binding domain reduced the antigen binding affinity, as reported by Archangeli et al ^[33]. Mild adverse events were demonstrated in the interim analysis of a phase 1 trial of rapidly switchable universal CAR-T (UniCAR) targeting CD123 ^[34]^[35]. Benmebarek and colleagues generated a controllable CAR platform-synthetic agonist receptor (SAR) T cells only activated in the presence of their CD33 or CD123 scFv construct in vitro and in AML xenograft models ^[36]. Dimerizing Agent Regulated ImmunoReceptor Complex (DARIC) is a split receptor design that modulates CAR T cell activation by rapamycin to dimerize units. This approach aims to aid hematopoietic recovery and mitigate toxicity. Cooper and colleagues developed a lentiviral DARIC construct that targets a C2 splice isoform with the membrane proximal domain of CD33, and a Phase I study using this strategy is now open for enrollment ^[37]. Researchers have recently demonstrated the potential benefits of DOX-inducible CAR-T therapy, allowing the control of CAR-T using an external trigger. It is an effective and sensitive way to turn CAR-T activity ON or OFF in order to prevent unwanted side effects and reduce prolonged toxicities ^[38]. Potentially, the most feasible approach is to knock out the targeted antigen in normal marrow cells. CD33 deletion in primary HSPCs maintained their full function in terms of engraftment and differentiation, and it efficiently reduced off-tumor targeting while preserving on-tumor efficacy ^[39]^[40].

3.3. Combinatorial Antigen Targeting for Heterogeneity

Combinations of CARs against different AML targets might be a promising solution due to the lack of a leukemia-specific target antigen ^[32]. Previously, promising results were reported with dual or tri-specific CAR T cells against B-cell malignancies and solid tumor models to overcome the heterogeneity and antigen escape ^[41]^[42]. Indeed, the phenomenon of ‘antigen escape’ as a reason of failure in CAR T cells for AML has not been clearly demonstrated in previous pre-clinical reports ^[43]^[44]. Nonetheless, regardless of antigen expression levels, dual-targeting CAR T cells were associated with increased T-cell activation and proliferation. This effect might be due to increased interaction with the target cell, favoring immune synapse formation and subsequent T cell recruitment ^[45]^[46]. How to combine suitable pairs of antigens to enhance therapeutic efficacy without increasing off-tumor toxicity are still pieces of the puzzle yet to be solved. Perna et al suggested four possible combinatorial pairings (CD33+ADGRE, CLEC12A+CCR1, CD33+CD70 and LILRB+CLEC12A) to target AML with an algorithm integrating proteomics and transcriptomics ^[25].

The combinatorial antigen targeting strategy has already been applied in AML. Bicistronic CD123 and CD33 CAR T cells showed significant anti-tumor activity in artificially created cell lines (CD33+CD123-, CD33-CD123+) and in vivo ^[47]. In a phase I trial, CLL-1 and CD33 bicistronic CAR T cells reported remarkable results ^[48]. Similarly, 10 of 11 pediatric R/R AML patients infused with CLL-1 or CLL-1-CD33 dual CAR T cells had a response (5 reached CR/MRD-) without dose-limiting toxicities ^[49]. Atilla et al reported that dual targeting with either a CD33 CAR or a CD123 CAR and a CLL-1 CAR increased anti-tumor activity most profoundly when the target antigen expression on the tumor cells was low. Since the expression of each target antigen is highly variable, researchers chose to modify T cells with two separate vectors targeting CLL-1 and CD33/CD123 to get a mixed product rather than a bicistronic or tandem CAR design in which the molar ratio of each target is fixed [80]. A universal CAR T cell platform (on/off switching mechanism) successfully targeted CD33 and CD123 positive AML blasts in vitro and in vivo ^[50]. Haubner et al presented a novel combinatorial ADGRE-2 targeting CAR and CLEC12A-targeting chimeric costimulatory receptor (CCR) (IF-BETTER gate) that triggered high anti-leukemic activity in vitro and in vivo while sparing vital normal hematopoietic cells ^[51].

3.4. Neoantigens

Neoantigens are limited to malignant clones that arise from somatic mutation ^[52]^[53]. Because recurrent gene alterations can be shared by AML patients, neoantigens trigger potent anti-leukemic responses ^[54]. Distinct from other cancers, AML presents with low mutational burden, so recognizing neoantigens arising from mutations is rare ^[55]^[56]. Neoantigens from driver gene mutations appear to be ideal targets for immunotherapy since immune evasion is unlikely ^[57].

3.5. T Cell Receptor (TCR) T Cells for Treatment of AML

T cell receptor (TCR) engineered T cells act through their modified TCRs and tumor-associated antigens (TAAs) presented by human leukocyte antigen (HLA) molecules on the surfaces of leukemic cells. The target protein can be expressed intracellularly or on the cell surface. TCR T cells have less stringent antigen requirements for T cell activation than CAR T cells ^[58]. TCR-T cell immunotherapy in AML has still barriers that need to be addressed. The major drawbacks are that TAAs might be expressed by non-malignant cells causing on-target, off-tumor toxicities, dose-related toxicity, limited persistence, and chance of immune escape ^[59]^[60]. Dose optimization of TCR-T cells, combining the treatment with exogenous cytokines (e.g., IL-21, IL-7 and IL-15), or adding genetically engineered signaling during cell expansion and demethylating agents such as decitabine might overcome the disadvantages of TCR-T cell application ^[61]. One other limitation of TCR transfer is the mispairing of endogenous and exogenous TCR components that impair the function; this limitation might be prevented by swapping the constant regions of mouse and human TCRs or codon-optimized cysteine modified TCRs in which TCR-α and β are linked by a T2A sequence ^[62]^[63]^[64]. Another approach uses TCR-like CAR T cells that contain scFv and CAR signaling mechanisms that recognize peptides in the context of MHC class I molecules ^[65].

3.6. CAR NK Cells

NK cells are lymphoid cells involved in the innate immune response; they are programmed to kill virus-infected and malignant cells without causing significant graft vs host disease, CRS or neurotoxicity ^[66]. AML has been an attractive target for NK cell therapy as an allogeneic product ^[67]. Despite several manipulations for longer persistence of NK cells, the response to NK cell infusions varies without long-term remissions ^[67]. NK cells differentiated into cytokine induced memory-like NK cells following stimulation with IL-12, IL-15 and IL-18 and showed a distinct transcriptional and surface proteomic profile as well as enhanced functionality ^[68]. Successful application of CD33-targeted CAR-modified NK cells by transduction of blood-derived primary NK cells showed promising cytotoxicity with unimpeded proliferation in vitro and in vivo without observable side effects ^[69].

3.7. Manipulations in Manufacturing

AML is a highly aggressive disease affecting older populations. In a relapsed refractory setting, patients receive many lines of immunosuppressive therapies prior to apheresis, which affects T cell function, and the timeline of manufacturing raises serious concerns in practice. Optimal CAR construct design will preserve the naïve and central memory phenotype as well as the persistence of T cells. It has been shown that naïve and early memory T-cells have been enriched by decitabine administered with CD123 CAR T-cells ^[70].

Administration of off-the shelf ready-to-use products (allogeneic CAR T cells) generated from healthy donors will provide a valuable solution, since the CAR-T cells product are pre-manufactured without need for customized manufacturing for a specific patient. DNA transposon systems are sophisticated systems for stable genetic modification that can deliver large genetic cargos and can be used to reduce cost ^[71]. Clinical-grade CAR-T cell products using Sleeping Beauty and piggyBac for multiple myeloma and leukemia are under investigation ^[72]^[73]^[74].

3.8. Strategies to Overcome the Negative Effects of Microenvironment

There are several approaches described to modulate immunosuppressive microenvironment. Immune evasion such as upregulating immune checkpoint proteins has proven to be a way which can dampen the antitumor response and limit efficacy of CAR-T cell therapy. Although immune checkpoint blockade in AML has not proven beneficial, ^[75]^[76]^[77] there may be still additional effects in combining CAR T cells and immune checkpoint blockage (PD-1, CTLA-4, etc) that will improve T cell persistence and anti-tumor efficacy ^[78].

3.9. Allogeneic Hematopoietic Stem Cell Transplantation with CAR T Cells

When and how to combine allo-HSCT with adoptive immunotherapy in AML is still debated. The mechanisms of resistance to T cell-mediated antitumor effects after allo-HSCT are well-defined in sophisticated murine models of allo-HSCT ^[79]. Combining a novel myeloablative irradiation-based conditioning regimen with regulatory and conventional T cell immunotherapy in haploidentical transplantation was shown to eradicate AML ^[80]. Published studies on how and when to combine CAR T cells in the setting of allo-HSCT showed conflicting results.

4. Summary and Conclusions

The tremendous advances in understanding the molecular and cellular mechanisms of AML have made it possible to manipulate the immune system and BM niches. Treating AML with CAR T cells is still in an immature stage. Experience with allogeneic stem cell transplantation, which is the most effective immune cellular therapy for AML, is guiding other directed therapies. One of the major challenges in developing CAR-T cell therapy for AML is the lack of a suitable antigen that is expressed uniquely on AML cells. Identifying and isolating target antigens that are homogeneously and stably expressed in all leukemic blasts and leukemic stem cells with limited on-target off-tumor toxicity, investigating complex interactions in the AML microenvironment, and seeking a suitable cell source all improve the fine-tuning of CARs.

Sophisticated methods for ex vivo manufacturing are now changing the in vivo dynamics and the character of the final product (Figure). In AML, personalization should be taken a step further in directed cellular therapies with platforms that will standardize the optimal CAR design for the target antigen or antigens in line with patient-specific immunophenotyping findings, the selection of a compatible carrier cell, and the cellular subtype.

References

Vishwasrao, P.; Li, G.; Boucher, J.C.; Smith, D.L.; Hui, S.K. Emerging CAR T Cell Strategies for the Treatment of AML. Cancers 2022, 14, 1241.
Schanz, J.; Tüchler, H.; Solé, F.; Mallo, M.; Luño, E.; Cervera, J.; Granada, I.; Hildebrandt, B.; Slovak, M.L.; Ohyashiki, K.; et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J. Clin. Oncol. 2012, 30, 820–829.
Kavanagh, S.; Murphy, T.; Law, A.; Yehudai, D.; Ho, J.M.; Chan, S.; Schimmer, A.D. Emerging therapies for acute myeloid leukemia: Translating biology into the clinic. J. Clin. Investig. 2017, 2, e95679.
Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute Myeloid Leukemia. N. Engl. J. Med. 2015, 373, 1136–1152.
Hofmann, S.; Schubert, M.-L.; Wang, L.; He, B.; Neuber, B.; Dreger, P.; Müller-Tidow, C.; Schmitt, M. Chimeric Antigen Receptor (CAR) T Cell Therapy in Acute Myeloid Leukemia (AML). J. Clin. Med. 2019, 8, 200.
Karamitros, D.; Stoilova, B.; Aboukhalil, Z.; Hamey, F.; Reinisch, A.; Samitsch, M.; Quek, L.; Otto, G.; Repapi, E.; Doondeea, J.; et al. Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat. Immunol. 2018, 19, 85–97.
Pollyea, D.A.; Jordan, C.T. Therapeutic targeting of acute myeloid leukemia stem cells. Blood 2017, 129, 1627–1635.
Chakraborty, S.; Park, C.Y. Pathogenic Mechanisms in Acute Myeloid Leukemia. Curr. Treat. Options Oncol. 2022, 23, 1522–1534.
Li, S.; Garrett-Bakelman, F.E.; Chung, S.S.; Sanders, M.A.; Hricik, T.; Rapaport, F.; Patel, J.; Dillon, R.; Vijay, P.; Brown, A.; et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat. Med. 2016, 22, 792–799.
Kreso, A.; Dick, J.E. Evolution of the cancer stem cell model. Cell Stem Cell 2014, 14, 275–291.
Thomas, D.; Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017, 129, 1577–1585.
Zeng, A.G.X.; Bansal, S.; Jin, L.; Mitchell, A.; Chen, W.C.; Abbas, H.A.; Chan-Seng-Yue, M.; Voisin, V.; van Galen, P.; Tierens, A.; et al. A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia. Nat. Med. 2022, 28, 1212–1223.
Sadelain, M. Chimeric antigen receptors: Driving immunology towards synthetic biology. Curr. Opin. Immunol. 2016, 41, 68–76.
LeBien, T.W.; Tedder, T.F. B lymphocytes: How they develop and function. Blood 2008, 112, 1570–1580.
Huntly, B.J.; Gilliland, D.G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat. Rev. Cancer 2005, 5, 311–321.
Dias, S.; Hattori, K.; Heissig, B.; Zhu, Z.; Wu, Y.; Witte, L.; Hicklin, D.J.; Tateno, M.; Bohlen, P.; Moore, M.A.S.; et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc. Natl. Acad. Sci. USA 2001, 98, 10857–10862.
Hussong, J.W.; Rodgers, G.M.; Shami, P.J. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000, 95, 309–313.
Mussai, F.; De Santo, C.; Abu-Dayyeh, I.; Booth, S.; Quek, L.; McEwen-Smith, R.M.; Qureshi, A.; Dazzi, F.; Vyas, P.; Cerundolo, V. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 2013, 122, 749–758.
Ben-Batalla, I.; Schultze, A.; Wroblewski, M.; Erdmann, R.; Heuser, M.; Waizenegger, J.S.; Riecken, K.; Binder, M.; Schewe, D.; Sawall, S.; et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 2013, 122, 2443–2452.
Austin, R.; Smyth, M.J.; Lane, S.W. Harnessing the immune system in acute myeloid leukaemia. Crit. Rev. Oncol. Hematol. 2016, 103, 62–77.
Epperly, R.; Gottschalk, S.; Velasquez, M.P. A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy. Front. Oncol. 2020, 10, 262.
Baragaño Raneros, A.; López-Larrea, C.; Suárez-Álvarez, B. Acute Myeloid Leukemia and NK Cells: Two Warriors Confront Each Other. OncoImmunology 2019, 8, e1539617.
Minnie, S.A.; Waltner, O.G.; Ensbey, K.S.; Nemychenkov, N.S.; Schmidt, C.R.; Bhise, S.S.; Legg, S.R.W.; Campoy, G.; Samson, L.D.; Kuns, R.D.; et al. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci. Immunol. 2022, 7, eabo3420.
Gomes-Silva, D.; Atilla, E.; Atilla, P.A.; Mo, F.; Tashiro, H.; Srinivasan, M.; Lulla, P.; Rouce, R.H.; Cabral, J.M.; Ramos, C.A.; et al. CD7 CAR T Cells for the Therapy of Acute Myeloid Leukemia. Mol. Ther. 2019, 27, 272–280.
Stratmann, S.; Vesterlund, M.; Umer, H.M.; Eshtad, S.; Skaftason, A.; Herlin, M.K.; Sundström, C.; Eriksson, A.; Höglund, M.; Palle, J.; et al. Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children. Leukemia 2023, 37, 550–559.
Trad, R.; Warda, W.; Alcazer, V.; da Rocha, M.N.; Berceanu, A.; Nicod, C.; Haderbache, R.; Roussel, X.; Desbrosses, Y.; Daguindau, E.; et al. Chimeric antigen receptor T-cells targeting IL-1RAP: A promising new cellular immunotherapy to treat acute myeloid leukemia. J. Immunother. Cancer 2022, 10, e004222.
Kirkey, D.C.; Loeb, A.M.; Castro, S.; McKay, C.N.; Perkins, L.; Pardo, L.; Leonti, A.R.; Tang, T.T.; Loken, M.R.; Brodersen, L.E.; et al. Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia. Blood Adv. 2023, 7, 1178–1189.
van Galen, P.; Hovestadt, V.; Wadsworth Ii, M.H.; Hughes, T.K.; Griffin, G.K.; Battaglia, S.; Verga, J.A.; Stephansky, J.; Pastika, T.J.; Lombardi Story, J.; et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell 2019, 176, 1265–1281.e24.
Jetani, H.; Navarro-Bailón, A.; Maucher, M.; Frenz, S.; Verbruggen, C.; Yeguas, A.; Vidriales, M.B.; González, M.; Rial Saborido, J.; Kraus, S.; et al. Siglec-6 Is a Novel Target for CAR T-Cell Therapy in Acute Myeloid Leukemia (AML). Blood 2021, 138, 1830–1842.
Hofmann, A.; Gerrits, B.; Schmidt, A.; Bock, T.; Bausch-Fluck, D.; Aebersold, R.; Wollscheid, B. Proteomic cell surface phenotyping of differentiating acute myeloid leukemia cells. Blood 2010, 116, e26–e34.
Köhnke, T.; Liu, X.; Haubner, S.; Bücklein, V.; Hänel, G.; Krupka, C.; Solis-Mezarino, V.; Herzog, F.; Subklewe, M. Integrated multiomic approach for identification of novel immunotherapeutic targets in AML. Biomark. Res. 2022, 10, 43.
Gottschlich, A.; Thomas, M.; Grünmeier, R.; Lesch, S.; Rohrbacher, L.; Igl, V.; Briukhovetska, D.; Benmebarek, M.-R.; Vick, B.; Dede, S.; et al. Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. Nat. Biotechnol. 2023; epub ahead of print.
Straathof, K.C.; Pule, M.A.; Yotnda, P.; Dotti, G.; Vanin, E.F.; Brenner, M.K.; Heslop, H.E.; Spencer, D.M.; Rooney, C.M. An inducible caspase 9 safety switch for T-cell therapy. Blood 2005, 105, 4247–4254.
Warda, W.; Da Rocha, M.N.; Trad, R.; Haderbache, R.; Salma, Y.; Bouquet, L.; Roussel, X.; Nicod, C.; Deschamps, M.; Ferrand, C. Overcoming target epitope masking resistance that can occur on low-antigen-expresser AML blasts after IL-1RAP chimeric antigen receptor T cell therapy using the inducible caspase 9 suicide gene safety switch. Cancer Gene Ther. 2021, 28, 1365–1375.
Tasian, S.K.; Kenderian, S.S.; Shen, F.; Ruella, M.; Shestova, O.; Kozlowski, M.; Li, Y.; Schrank-Hacker, A.; Morrissette, J.J.; Carroll, M.; et al. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood 2017, 129, 2395–2407.
Simon, S.; Bugos, G.; Salter, A.I.; Riddell, S.R. Synthetic receptors for logic gated T cell recognition and function. Curr. Opin. Immunol. 2022, 74, 9–17.
Arcangeli, S.; Rotiroti, M.C.; Bardelli, M.; Simonelli, L.; Magnani, C.F.; Biondi, A.; Biagi, E.; Tettamanti, S.; Varani, L. Balance of anti-Cd123 chimeric antigen receptor binding affinity and density for the targeting of acute myeloid leukemia. Mol. Ther. 2017, 25, 1933–1945.
Loff, S.; Dietrich, J.; Meyer, J.-E.; Riewaldt, J.; Spehr, J.; von Bonin, M.; Gründer, C.; Swayampakula, M.; Franke, K.; Feldmann, A.; et al. Rapidly switchable universal car-T cells for treatment of Cd123-positive leukemia. Mol. Ther. Oncol. 2020, 17, 408–420.
Wermke, M.; Kraus, S.; Ehninger, A.; Bargou, R.C.; Goebeler, M.E.; Middeke, J.M.; Kreissig, C.; von Bonin, M.; Koedam, J.; Pehl, M.; et al. Proof of concept for a rapidly switchable universal car-T platform with unicar-T-Cd123 in Relapsed/Refractory aml. Blood 2021, 137, 3145–3148.
Benmebarek, M.-R.; Cadilha, B.L.; Herrmann, M.; Lesch, S.; Schmitt, S.; Stoiber, S.; Darwich, A.; Augsberger, C.; Brauchle, B.; Rohrbacher, L.; et al. A modular and controllable T cell therapy platform for acute myeloid leukemia. Leukemia 2021, 35, 2243–2257.
Cooper, T.M.; Wu, V.; Wilson, A.; Appelbaum, J.; Jarjour, J.; Gustafson, J.; Mgebroff, S.; Lindgren, C.; Brown, C.; Jensen, M.C.; et al. Pediatric and young adult leukemia adoptive therapy (PLAT)-08: A phase 1 study of SC-DARIC33 in pediatric and young adults with relapsed or refractory CD33+AML. J. Clin. Oncol. 2022, 40, TPS7078.
Fernández, L.; Fernández, A.; Mirones, I.; Escudero, A.; Cardoso, L.; Vela, M.; Lanzarot, D.; De Paz, R.; Leivas, A.; Gallardo, M.; et al. GMP-Compliant Manufacturing of NKG2D CAR Memory T Cells Using CliniMACS Prodigy. Front. Immunol. 2019, 10, 2361.
Kim, M.Y.; Yu, K.R.; Kenderian, S.S.; Ruella, M.; Chen, S.; Shin, T.H.; Aljanahi, A.A.; Schreeder, D.; Klichinsky, M.; Shestova, O.; et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 2018, 173, 1439–1453.e19.
Liu, Y.; Wang, S.; Schubert, M.L.; Lauk, A.; Yao, H.; Blank, M.F.; Cui, C.; Janssen, M.; Schmidt, C.; Göllner, S.; et al. CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Int. J. Cancer 2022, 150, 1141–1155.
Kailayangiri, S.; Altvater, B.; Wiebel, M.; Jamitzky, S.; Rossig, C. Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers. Cancers 2020, 12, 1075.
Schneider, D.; Xiong, Y.; Wu, D.; Hu, P.; Alabanza, L.; Steimle, B.; Mahmud, H.; Anthony-Gonda, K.; Krueger, W.; Zhu, Z.; et al. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci. Transl. Med. 2021, 13, eabc6401.
Atilla, P.A.; McKenna, M.K.; Watanabe, N.; Mamonkin, M.; Brenner, M.K.; Atilla, E. Combinatorial antigen targeting strategies for acute leukemia: Application in myeloid malignancy. Cytotherapy 2022, 24, 282–290.
Damiani, D.; Tiribelli, M. Present and Future Role of Immune Targets in Acute Myeloid Leukemia. Cancers 2022, 15, 253.
Xiong, W.; Chen, Y.; Kang, X.; Chen, Z.; Zheng, P.; Hsu, Y.H.; Jang, J.H.; Qin, L.; Liu, H.; Dotti, G.; et al. Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells. Mol. Ther. 2018, 26, 963–975.
Petrov, J.C.; Wada, M.; Pinz, K.G.; Yan, L.E.; Chen, K.; Shuai, X.; Liu, H.; Chen, X.; Leung, L.-H.; Salman, H.; et al. Compound CAR Tcells as a double-pronged approach for treating acute myeloid leukemia. Leukemia 2018, 32, 1317–1326.
Liu, F.; Cao, Y.; Pinz, K.; Ma, Y.; Wada, M.; Chen, K.; Ma, G.; Shen, J.; Tse, C.O.; Su, Y.; et al. First-in-Human CLL1-CD33 Compound CAR T Cell Therapy Induces Complete Remission in Patients with Refractory Acute Myeloid Leukemia: Update on Phase 1 Clinical Trial. Blood 2018, 132, 901.
Zhang, H.; Bu, C.; Peng, Z.; Luo, M.; Li, C. The efficacy and safety of anti-CLL1 based CAR-T cells in children with relapsed or refractory acute myeloid leukemia: A multicenter interim analysis. J. Clin. Oncol. 2021, 39 (Suppl. 15), 10000.
Cartellieri, M.; Feldmann, A.; Koristka, S.; Arndt, C.; Loff, S.; Ehninger, A.V.; Von Bonin, M.; Bejestani, E.P.; Ehninger, G.; Bachmann, M.P. Switching CAR T cells on and off: A novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016, 6, e458.
Haubner, S.; Mansilla-Soto, J.; Nataraj, S.; Kogel, F.; Chang, Q.; De Stanchina, E.; Fraser, K.; Park, J.H.; Wang, X.; Rivière, I.; et al. Target Densities in Malignant and Normal Cells Determine CAR T Cell Efficacy and Off-Target Hematotoxicity. Blood 2022, 140 (Suppl. 1), 869–870.
Blass, E.; Ott, P.A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 2021, 18, 215–229.
Blankenstein, T.; Leisegang, M.; Uckert, W.; Schreiber, H. Targeting cancer specific mutations by T cell receptor gene therapy. Curr. Opin. Immunol. 2015, 33, 112–119.
Tran, E.; Robbins, P.F.; Lu, Y.-C.; Prickett, T.D.; Gartner, J.J.; Jia, L.; Pasetto, A.; Zheng, Z.; Ray, S.; Groh, E.M.; et al. T-Cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 2016, 375, 2255–2262.
van der Lee, D.I.; Reijmers, R.M.; Honders, M.W.; Hagedoorn, R.S.; de Jong, R.C.; Kester, M.G.; van der Steen, D.M.; de Ru, A.H.; Kweekel, C.; Bijen, H.M.; et al. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia. J. Clin. Investig. 2019, 129, 774–785.
Graf, C.; Heidel, F.; Tenzer, S.; Radsak, M.P.; Solem, F.K.; Britten, C.M.; Huber, C.; Fischer, T.; Wölfel, T. A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells. Blood 2007, 109, 2985–2988.
Harris, D.T.; Kranz, D.M. Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors. Trends Pharmacol. Sci. 2016, 37, 220–230.
Coulie, P.G.; Van den Eynde, B.J.; Van Der Bruggen, P.; Boon, T. Tumour antigens recognized by T lymphocytes: At the core of cancer immunotherapy. Nat. Rev. Cancer 2014, 14, 135–146.
Rosenberg, S.A.; Restifo, N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015, 348, 62.
Kang, S.; Li, Y.; Qiao, J.; Meng, X.; He, Z.; Gao, X.; Yu, L. Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges. Front. Oncol. 2022, 12, 787108.
Xue, S.; Gillmore, R.; Downs, A.; Tsallios, A.; Holler, A.; Gao, L.; Wong, V.; Morris, E.; Stauss, H.J. Exploiting T cell receptor genes for cancer immunotherapy. Clin. Exp. Immunol. 2005, 139, 167–172.
Cohen, C.J.; Zhao, Y.; Zheng, Z.; Rosenberg, S.A.; Morgan, R.A. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res. 2006, 66, 8878–8886.
van Balen, P.; Jedema, I.; van Loenen, M.M.; de Boer, R.; van Egmond, H.M.; Hagedoorn, R.S.; Hoogstaten, C.; Veld, S.A.J.; Hageman, L.; van Liempt, P.A.G.; et al. HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study. Front. Immunol. 2020, 11, 1804.
Bald, T.; Krummel, M.F.; Smyth, M.J.; Barry, K.C. The NK cell-cancer cycle: Advances and new challenges in NK cell-based immunotherapies. Nat. Immunol. 2020, 21, 835–847.
Sivori, S.; Pende, D.; Quatrini, L.; Pietra, G.; Della Chiesa, M.; Vacca, P.; Tumino, N.; Moretta, F.; Mingari, M.C.; Locatelli, F.; et al. NK cells and ILCs in tumor immunotherapy. Mol. Asp. Med. 2021, 80, 100870.
Liu, E.; Marin, D.; Banerjee, P.; Macapinlac, H.A.; Thompson, P.; Basar, R.; Nassif Kerbauy, L.; Overman, B.; Thall, P.; Kaplan, M.; et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N. Engl. J. Med. 2020, 382, 545–553.
Huang, R.; Wen, Q.; Wang, X.; Yan, H.; Ma, Y.; Wang, M.-H.; Han, X.; Gao, L.; Gao, L.; Zhang, C.; et al. Off-the-Shelf CD33 CAR-NK Cell Therapy for Relapse/Refractory AML: First-in-Human, Phase I Trial. Blood 2022, 140 (Suppl. 1), 7450–7451.
Hudecek, M.; Ivics, Z. Non-viral therapeutic cell engineering with the Sleeping Beauty transposon system. Curr. Opin. Genet. Dev. 2018, 52, 100–108.
Costello, C.L.; Gregory, T.K.; Ali, S.A.; Berdeja, J.G.; Patel, K.K.; Shah, N.D.; Ostertag, E.; Martin, C.; Ghoddusi, D.M.; Shedlock, D.J.; et al. Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME). Blood 2019, 134, 3184.
Magnani, C.F.; Gaipa, G.; Lussana, F.; Belotti, D.; Gritti, G.; Napolitano, S.; Matera, G.; Cabiati, B.; Buracchi, C.; Borleri, G.; et al. Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. J. Clin. Investig. 2020, 130, 6021–6033.
Prommersberger, S.; Reiser, M.; Beckmann, J.; Danhof, S.; Amberger, M.; Quade-Lyssy, P.; Einsele, H.; Hudecek, M.; Bonig, H.; Ivics, Z. CARAMBA: A first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Ther. 2021, 28, 560.
Daver, N.; Basu, S.; Garcia-Manero, G.; Cortes, J.E.; Ravandi, F.; Jabbour, E.J.; Hendrickson, R.S.; Pierce, B.S.; Ning, J.; Konopleva, M.; et al. Phase IB/II study of nivolumab in combination wth azacytidine in patients with relapsed acute myeloid leukemia. Blood 2016, 22, 763.
Davids, M.S.; Kim, H.T.; Bachireddy, P.; Costello, C.; Liguori, R.; Savell, A.; Lukez, A.P.; Avigan, D.; Chen, Y.-B.; McSweeney, P.; et al. Ipilimumab for patients with relapse after allogeneic transplantation. N. Engl. J. Med. 2016, 375, 143–153.
Kadia, T.M.; Cortes, J.E.; Ghorab, A.; Ravandi, F.; Jabbour, E.; Daver, N.G.; Alvarado, Y.; Ohanian, M.; Konopleva, M.; Kantarjian, H.M. Nivolumab maintenance in high-risk acute myeloid leukemia patients. J. Clin. Oncol. 2018, 36, 15.
Jitschin, R.; Saul, D.; Braun, M.; Tohumeken, S.; Völkl, S.; Kischel, R.; Lutteropp, M.; Dos Santos, C.; Mackensen, A.; Mougiakakos, D. CD33/CD3-bispecific T-cell engaging (BiTE R ) antibody construct targets monocytic AML myeloid-derived suppressor cells. J. Immunother. Cancer 2018, 6, 116.
Pan, J.; Yang, J.F.; Deng, B.P.; Zhao, X.J.; Zhang, X.; Lin, Y.H.; Wu, Y.N.; Deng, Z.L.; Zhang, Y.L.; Liu, S.H.; et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia 2017, 31, 2587–2593.
Hay, K.A.; Gauthier, J.; Hirayama, A.V.; Voutsinas, J.M.; Wu, Q.; Li, D.; Gooley, T.A.; Cherian, S.; Chen, X.; Pender, B.S.; et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood 2019, 133, 1652–1663.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Cell & Tissue Engineering

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Erden Atilla

Karim Benabdellah

View Times: 415

Update Date: 29 May 2023

Table of Contents

Video Upload Options

Confirm