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Target Overview
KRAS mutations are among the most prevalent mutations observed in cancers and have been shown to drive tumor development and growth. KRAS G12D is the most prominent mutation in PDAC, with a frequency of approximately 28%. It is also present in approximately 12% of colorectal adenocarcinomas and 4% of NSCLC. Peptides encoding KRAS mutations can be presented by different HLAs. For example, the KRAS G12D variant can be presented by HLA-A*11:01/11:02, an HLA type with a frequency of approximately 10% in the Caucasian population in at least one allele.
The AZD0240 TCR was originally identified in a 48-year-old colorectal cancer patient (Patient 4373) enrolled in a Phase 2 clinical trial (NCT03412877) at the NCI, which was designed to test whether adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TIL) containing T cells targeting personalized cancer neoepitopes can mediate regression of metastatic solid cancers.1
Compound Overview
AZD0240 is an investigational immunotherapy that consists of autologous T-cells derived from a patient's own immune cells that express a T-cell receptor recognizing mutated KRAS G12D in the context of HLA-A*11:01/11:02.2 The T-cells are armored through the genetic knock-out of Cbl proto-oncogene B (CBLB), which deletes a negative regulator of TCR signaling and enhances anti-tumor efficacy. In addition, T-cells are armored through the genetic knock-in of the cluster of differentiation 8A (CD8A) and CD8B genes encoding CD8αβ, which increases function of the HLA class I-restricted AZD0240 TCR in CD4+ T cells.
Using our proprietary non-viral nuclease-based engineered T-cell manufacturing platform, AZD0240 is manufactured at AstraZeneca’s internal manufacturing facility in Santa Monica.
Mechanism of Action
References
1. Tran E, et al. N Engl J Med. 2016;375(23):2255-2226. 2. Huang L, Guo Z, Wang F, Fu L. Signal Transduct Target Ther. 2021;6(1):386.
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Abbreviations
CBLB
Cbl proto-oncogene B
CD8A
cluster of differentiation 8A
CD8B
cluster of differentiation 8B
CD8αβ
cluster of differentiation 8αβ
CD4+
cluster of differentiation 4+
HLA
human leukocyte antigen
KRAS
Kirsten rat sarcoma viral oncogene homolog
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
PDAC
pancreatic ductal adenocarcinoma
TCR
T-cell receptor
CBLB
Cbl proto-oncogene B
CD8αβ
cluster of differentiation 8 alpha beta
TILs
tumor-infiltrating lymphocytes
Target Overview
KRAS mutations are among the most prevalent mutations observed in cancers and have been shown to drive tumor development and growth. KRAS G12D is the most prominent mutation in PDAC, with a frequency of approximately 28%. It is also present in approximately 12% of colorectal adenocarcinomas and 4% of NSCLC. Peptides encoding KRAS mutations can be presented by different HLAs. For example, the KRAS G12D variant can be presented by HLA-A*11:01/11:02, an HLA type with a frequency of approximately 10% in the Caucasian population in at least one allele.
The AZD0240 TCR was originally identified in a 48-year-old colorectal cancer patient (Patient 4373) enrolled in a Phase 2 clinical trial (NCT03412877) at the NCI, which was designed to test whether adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TIL) containing T cells targeting personalized cancer neoepitopes can mediate regression of metastatic solid cancers.1
Compound Overview
AZD0240 is an investigational immunotherapy that consists of autologous T-cells derived from a patient's own immune cells that express a T-cell receptor recognizing mutated KRAS G12D in the context of HLA-A*11:01/11:02.2 The T-cells are armored through the genetic knock-out of Cbl proto-oncogene B (CBLB), which deletes a negative regulator of TCR signaling and enhances anti-tumor efficacy. In addition, T-cells are armored through the genetic knock-in of the cluster of differentiation 8A (CD8A) and CD8B genes encoding CD8αβ, which increases function of the HLA class I-restricted AZD0240 TCR in CD4+ T cells.
Using our proprietary non-viral nuclease-based engineered T-cell manufacturing platform, AZD0240 is manufactured at AstraZeneca’s internal manufacturing facility in Santa Monica.
Mechanism of Action
References
1. Tran E, et al. N Engl J Med. 2016;375(23):2255-2226. 2. Huang L, Guo Z, Wang F, Fu L. Signal Transduct Target Ther. 2021;6(1):386.
Clinical trial information
Select trial for more information
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Abbreviations
CBLB
Cbl proto-oncogene B
CD8A
cluster of differentiation 8A
CD8B
cluster of differentiation 8B
CD8αβ
cluster of differentiation 8αβ
CD4+
cluster of differentiation 4+
HLA
human leukocyte antigen
KRAS
Kirsten rat sarcoma viral oncogene homolog
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
PDAC
pancreatic ductal adenocarcinoma
TCR
T-cell receptor
CBLB
Cbl proto-oncogene B
CD8αβ
cluster of differentiation 8 alpha beta
TILs
tumor-infiltrating lymphocytes