The safety and efficacy of Celgene's CAR T cell therapies are under investigation and have not been established. There is no guarantee that these agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Cancer Immune Response

Refresh your knowledge about the immune response to cancer, and how cancer can evade detection

CAR T Science

Learn about the science behind CAR T cell therapies

B Cell Malignancies

Learn about unmet needs in select B cell malignancies

CAR T Process

Learn what the CAR T therapy process may involve for you and your patients

Adoptive Immunotherapy for Select B Cell Malignancies

CAR T cell therapy involves the infusion of T cells that have been genetically engineered to express a chimeric antigen receptor (CAR) to reprogram the T cells. The CAR combines the specificity of a monoclonal antibody with the cytotoxic and memory functions of T cells.1

CAR specificity comes from the extracellular domain, which is derived from the antigen-binding site of a monoclonal antibody.2,3 The intracellular domain attempts to recapitulate the normal series of events by which T cells are activated and incorporates stimulatory and costimulatory domains, such as CD28 or 4-1BB (CD137), to augment CAR T cell survival and proliferation.1,4-6

Because CAR T cells carry their own co-stimulatory signaling, they may be less susceptible than unmodified T cells to negative regulation from tumors.1 Unlike T cell receptors, CAR T cells do not rely on dendritic cell antigen processing and presentation.7 In addition, CAR T cells may multiply and differentiate into central or effector memory cells, and have been observed to persist in the body for 30 days up to four years after administration.6,8,9

Autologous CAR T cell therapies are created from the patient’s own T cells. The production processes used to create CAR T cell therapies are specific to each manufacturer, making each CAR T cell therapy unique.

CAR Structure and Function

  • 1
  • 2
  • 3
  • 4
1234

1Target antigen-

1. Target antigen; 2. External targeting domain; 3. Transmembrane domain; 4. Co-stimulatory domain

A variety of antigen types are being investigated in B cell hematologic tumors.10 B cell malignancies express several potential antigen targets:

  • CD19, a B cell antigen found on the surface of B cells, including malignant cells and normal cells.10-12
  • B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17). BCMA is a cell surface protein universally expressed on plasma cells including both malignant and normal, healthy cells.13
  • Other investigational B cell antigen targets have included CD20, CD22, CD23, ROR1, and the kappa light chain.14

2External targeting domain+

1. Target antigen; 2. External targeting domain; 3. Transmembrane domain; 4. Co-stimulatory domain

The targeting domain is derived from a monoclonal antibody and recognizes a specific antigen. A single-chain variable fragment is generated by linking the variable region heavy and light chains. This domain allows the T cell to bind to the antigens and does not rely on dendritic cell antigen processing and presentation. Binding of the targeting domain to the target antigen triggers T cell activation.10,15

Spacer/hinge

Connects the extracellular targeting element to the transmembrane domain and affects CAR function and scFv flexibility.16,17

3Transmembrane domain+

1. Target antigen; 2. External targeting domain; 3. Transmembrane domain; 4. Co-stimulatory domain

The transmembrane domain may influence CAR expression on the surface of the T cell.7

4Co-stimulatory domain+

1. Target antigen; 2. External targeting domain; 3. Transmembrane domain; 4. Co-stimulatory domain

These domains provide the co-stimulatory signal required for full T cell activation. Some evidence suggests that co-stimulatory domains may increase CAR T cell cytokine production and facilitate T cell replication. Co-stimulatory domains have also been shown to potentially reduce CAR T cell exhaustion, increase T cell antitumor activity, and enhance survival of CAR T cells in patients.7

These topics are discussed in more detail below in CAR T cell Expansion and Persistence.

CD3 zeta signaling domain

The intracellular portion of the CAR also includes the signaling domain, typically the TCR complex CD3 zeta.

PREV
NEXT

CAR T Cell Expansion and Persistence

Expansion and persistence of CAR T cells in the body are linked to several important factors.4

Co-stimulatory Signaling

Co-stimulatory signaling is thought to influence T cell expansion, metabolic profile, persistence, and subset composition.6 All approved CAR constructs currently available use one of two co-stimulatory domains: CD28 or 4-1BB.16 Investigational co-stimulatory domains currently in pre-clinical and clinical studies include inducible co-stimulator (ICOS), OX40, CD27, CD28, and 4-1BB.14

CD28 co-stimulatory signaling in preclinical studies has been associated with6,18,19:

  • Higher proportion of effector memory T cells, which rapidly differentiate into short-lived effector T cells
  • Rapid effector function
  • Short persistence

CAR T cells using 4-1BB co-stimulatory signaling in preclinical studies has been associated with6,18,19:

  • Higher proportion of central memory T cells, which are less differentiated and more able to proliferate than effector memory cells
  • Slower, sustained effector function
  • Long persistence

The impact of co-stimulatory domain selection on clinical outcomes is unknown.

T cell selection and composition

CD4 and CD8 T cells are functionally distinct subsets that differ in their ability to proliferate and persist in the body.20 The manufacturing process for some CAR T cell therapies adjusts T cell subtypes to provide a consistent composition. The clinical importance of T cell composition in CAR T cell therapy is unknown.20

Ex vivo expansion

CAR T cells are expanded, or grown, outside the body to an appropriate therapeutic dose.21 Some studies have also reported a correlation between CAR T cell dose and the incidence and severity of cytokine-release syndrome (CRS) and neurotoxicity, especially in patients with higher levels of disease burden at the time of infusion.21,22 The impact of CAR T cell dose on safety outcomes is unknown and may differ between products and disease states.

Learn about CAR T cell therapy administration and monitoring

How CAR T Cell Therapy Is Thought to Work

While the mechanism of action is not fully understood, evidence suggests that CAR T cell therapies stimulate a T cell response against antigen-expressing cells, including normal and malignant cells. The external targeting domain binds to the antigen, activating the CAR T cell. Once activated, CAR T cells release cytokines and other soluble mediators that may directly kill antigen-expressing target cells and normal cells.1,10

WATCH CAR T CELL THERAPY IN ACTION  
×

References:

  1. Maus MV, Levine BL. Oncologist. 2016;21:608-617.
  2. Dotti G, Gottschalk S, Savoldo B, et al. Immunol Rev. 2014;257:107-126.
  3. Sadelain M, Brentjens R, Rivière I. Cancer Discov. 2013;3:388-398.
  4. Ajina A, Maher J. Mol Cancer Ther. 2018;17:1795-1815.
  5. Maus MV, June CH. Clin Cancer Res. 2016;22:1875-1884.
  6. Kawalekar OU, O'Connor RS, Fraietta JA, et al. Immunity. 2016;44:380-390.
  7. Dai H, Wang Y, Lu X, Han W. J Natl Cancer Inst. 2016;108:1-14.
  8. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia, PA: Saunders Elsevier; 2018.
  9. Porter DL, Hwang WT, Frey NV, et al. Sci Transl Med. 2015;7:303ra139.
  10. Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz, CJ. EMBO Mol Med. 2017;9:1183-1197.
  11. Tai YT, Anderson KC. Immunotherapy. 2015;7:1187-1199.
  12. Park JH, Brentjens RJ. Discov Med. 2010;9:277-288.
  13. Tai YT, Mayes PA, Acharya C, et al. Blood. 2014;123:3128-3138.
  14. D’Aloia MM, Zizzari IG, Sacchetti B, et al. Cell Death Dis. 2018;9:282.
  15. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. Nat Rev Clin Oncol. 2016;13:273-290.
  16. Abate-Daga D, Davila ML. Mol Ther Oncolytics. 2016;3:16014.
  17. Watanabe N, Bajgain P, Sukumaran S, et al. Oncoimmunology. 2016;5:e1253656.
  18. Zhao Z, Condomines M, van der Stegen SJ, et al. Cancer Cell. 2015;28:415-428.
  19. Mahnke YD, Brodie TM, Sallusto F, et al. Eur J Immunol. 2013;43:2797-2809.
  20. Turtle CJ, Hanafi LA, Berger C, et al. J Clin Invest. 2016;126:2123-2138.
  21. Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13:25-40.
  22. Park JH, Geyer MB, Brentjens RJ. Blood. 2016;127:3312-3320.

This website is intended for US healthcare professionals only. Are you a US healthcare professional?

NO
YES