CAR T-Cells in Multiple Myeloma Are Ready for Prime Time
Abstract
:1. Introduction
2. Engineered T-Cells in MM: CAR T-Cells
3. Target Selection
- (1)
- CD38 is expressed with high intensity in clonal plasma cells and has been shown to be a promising target for the treatment of MM. However, CD38 is also expressed, although with less intensity, on normal hematopoietic cells, such as red blood cells, natural killer cells, and other tissues, increasing the risk of on-target off-tumor toxicity [11]. There is already preclinical evidence showing an activity of CD38-targeting CAR T-cells, and several clinical trials are ongoing.
- (2)
- CD138 (Syndecan 1) is expressed in normal and clonal plasma cells and also on normal tissues such as epithelial cells potentially inducing “on target–off tumor” toxicity. However, in a preclinical study using CD138-directed CAR T-cells, no epithelial toxicity was observed [12]. The same experience was noted in a clinical report with five patients treated with CD138 directed CAR T-cell in China, and a phase 1 trial is ongoing [11].
- (3)
- The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), is expressed ubiquitously in malignant bone marrow plasma cells, hair follicles, and variably in the lung tissue [13]. Interestingly, expression in MM cells is 500 to 1000 times that found on normal cells [11]. CAR T-cells targeting GPRC5D have demonstrated promising preclinical activity [13], and clinical strategies targeting GPRC5D, particularly using bispecific antibodies, are under evaluation.
- (4)
- Signaling lymphocyte activation molecule F7 (SLAMF7 or CS1) is widely expressed on plasma cells, as well as subsets of normal B and T-cells, natural killer (NK) cells, monocytes, and dendritic cells, and it is already a target used in MM therapy with the antibody elotuzumab [11,14,15]. CAR T-cells targeting SLAMF7 have shown encouraging preclinical activity; however, SLAMF7 expression in lymphocyte subsets raised the problem of the specific fratricide of SLAMF7+/high target cells by SLAMF7-CAR T-cells, although SLAMF7−/low was preserved and able to remain viable [16]. Clinical trials evaluating SLAMF7-targeted CAR T-cells are ongoing.
- (5)
- CD19-directed CAR T-cell therapy is approved for the treatment of B acute lymphoblastic leukemia and diffuse large B cell lymphoma. CD19 is typically absent on the dominant multiple myeloma cell population, but it may be present on a minor subset with unique myeloma-propagating properties [17,18]. CD19-directed CAR T-cell therapy has been tested in MM patients after autologous stem cells therapy with interesting results [18] and also in combination with BCMA-directed CAR T-cells in small series of patients with promising data [19].
- (6)
- The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, γδ+, and CD8+ T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but they are frequently expressed by tumor cell lines and in tumor tissues, which makes them attractive targets for CAR development [20]. NKG2D ligand-directed CAR T-cells have been evaluated both in preclinical and clinical settings (albeit a small number of patients) with promising results [21]. NKG2D ligand-directed CAR NK cells are also under development [22].
4. Clinical Data Using CAR T-Cells in MM
5. Limitations of Current Approaches and Potential Avenues
5.1. Peak Expansion and Response
5.2. Antigen Escape
5.3. CAR T-Cell Persistence and Duration of Response
5.4. Combination Therapies
6. Practical Considerations
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Antigen | Expression in Plasma Cells | Function | Off-Target Expression | Ongoing Trials |
---|---|---|---|---|
BCMA | Universal in plasma cells | Membrane bound of the TNFR superfamily | Restricted to B-cell compartment | NCT04309981 NCT03430011 NCT03288493 NCT04181827 NCT04133636 NCT04093596 NCT04196491 NCT03601078 NCT03651128 NCT04244656 NCT04394650 |
CD38 (Syndecan 1) | Overexpressed in multiple myeloma cells | As a receptor, CD38 can bind CD31 in T cells, activating them. As an enzyme, it catalyzes the synthesis and hydrolysis of cyclic ADP-ribose. | Normal hematopoietic cells: red blood cells, NK cells | NCT03464916 NCT03473496 NCT03767751 |
GPRC5D | Universal in plasma cells | Not yet been determined | Hair follicle and lung tissue | NCT04555551 |
SLAMF7 | Overexpressed in multiple myeloma cells | Mediates activating or inhibitory effects in NK cells | Normal B and T-cells, NK-cells, monocytes, and dendritic cells | NCT04499339 |
CD19 | Rarely detected in plasma cells | Involved in B-cell maturation | All B-lineage cells | NCT04194931 NCT04182581 NCT03767725 NCT04236011 NCT03455972 NCT04162353 * |
NKG2D | Not expressed in plasma cells | Important role in the NK, γδ+, and CD8+ T-cell-mediated immune response to tumors | Rarely detectable on healthy cells and tissues | Under development |
Idecabtagene Vicleucel (Ide-Cel) KARMMA Study [23] | bb21217 [24] | Orvacabtagene-Autoleucel (Orva-Cel) EVOLVE Ph 1/2 Trial [25] | Ciltacabtagene Autoleucel (Cilta-Cel) CARTITUDE 1 [26] | LCAR-B38M LEGEND-2 [27] | |
---|---|---|---|---|---|
CAR Design | Autologous, lentiviral vector 4-1BB | Ide-cel cultured with PI3Ki, to enrich memory-like T cells | Fully human (CD28/41BB). 1:1 CD4:CD8 ratio | 2 BCMA-targeting single chain antibody | 2 BCMA-targeting single chain antibody (same as JNJ 4528) |
Population | 128 (Ph 2) | 38 (Ph 1) | 62 (Ph 1/2) | 29 (Ph 1b/2) | 57 (Ph 2) |
Number of Prior lines | 6 | 6 | 6 | 5 | 2 |
CAR T-cell Dose | 150–450 × 106 CAR T-cell | 150–450 × 106 CAR T-cell | 300–600 × 106 CAR T-cell | 0.73 × 106 CAR T-cells/kg | 0.5 × 106 CAR T + Cells/kg |
Refractory to CD38 MoAb | 94% | 76% | NA | 93% | 1 patients |
Triple-class Refractory | 84% | 63% | 94% | 86% | -- |
Extramedullar disease | 39% | NA | 23% | 10% | NA |
ORR (CR) | 82%* (39%) | NA (33%) | 92% #. (29%) | 100% (86%) | 88% (74%) |
DOR/PFS/ OS months | 11.3 */12.1 */19.4 | 11.1 &/NA/NA | NA/NA/ NA | NA/86%@9m/NA | 19.9m In CR: mPFS 28.2 m |
CRS (G 3/4) | 96% * (6%) | 66% (6%) | 88% # (4%) | 93% (7%) | 90% (7%) |
Neurotox(G3) | 20% * (6%) | 24% (8%) | 13% # (0%) | 10% (3%) | 2% |
Reference | (1) Munshi NC, et al. Initial KarMMa results. J Clin Oncol. 2020;38 (suppl; abstr 8503). | (2) Berdeja JG, et al. Blood (Internet). 2019 Nov 13;134 (Supplement_1):927. | (3) Mailankody S, et al. J Clin Oncol. 2020;30 (suppl; abstr 8504). | (4) Usmani SZ, et al. EHA Library. 2020. p. EP926. | (5) Chen L, et al. Blood (Internet) 2019 Nov 13;134 (Supplement_1):1858. |
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Rodríguez-Otero, P.; Prósper, F.; Alfonso, A.; Paiva, B.; San Miguel, J.F. CAR T-Cells in Multiple Myeloma Are Ready for Prime Time. J. Clin. Med. 2020, 9, 3577. https://doi.org/10.3390/jcm9113577
Rodríguez-Otero P, Prósper F, Alfonso A, Paiva B, San Miguel JF. CAR T-Cells in Multiple Myeloma Are Ready for Prime Time. Journal of Clinical Medicine. 2020; 9(11):3577. https://doi.org/10.3390/jcm9113577
Chicago/Turabian StyleRodríguez-Otero, Paula, Felipe Prósper, Ana Alfonso, Bruno Paiva, and Jesús F. San Miguel. 2020. "CAR T-Cells in Multiple Myeloma Are Ready for Prime Time" Journal of Clinical Medicine 9, no. 11: 3577. https://doi.org/10.3390/jcm9113577