Development and optimization of PSCA-specific CAR T cells for the treatment of bone metastatic prostate cancer
Gerdts et al. Journal for ImmunoTherapy of Cancer
Development and optimization of PSCA-specific CAR T cells for the treatment of bone metastatic prostate cancer
Ethan Gerdts 1 2
Saul Priceman 1 2
Dileshni Tilakawardane 1 2
Anthony Park 1 2
Wen-Chung Chang 1 2
Sarah Wright 1 2
Christine E Brown 0 2
Stephen J Forman 0 2
0 Beckman Research Institute, City of Hope National Medical Center , Duarte, CA , USA
1 City of Hope National Medical Center , Duarte, CA , USA
2 Authors' details
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Prostate Cancer (PCa) is the third most common cancer
type in the United States, with over 200,000 new cases
projected to be diagnosed this year. In approximately
80% of PCa patients, tumor phenotype includes
overexpression of prostate stem cell antigen, or PSCA.
Furthermore, PSCA is expressed on nearly 100% of
bone metastatic prostate cancers, making it an attractive
immunotherapeutic target. We have genetically
engineered T cells to express chimeric antigen receptors
(CARs) which specifically target PSCA. Recent clinical
trials with CARs targeting CD19 for B-cell malignancies
have demonstrated impressive results, yet replicating
this success with other antigen targets remains elusive.
Immunotherapy against solid tumors poses a more
difficult tumor challenge because of the immunosuppressive
microenvironment that can significantly hinder CAR
efficacy. Additionally, there have been instances of
ontarget, off-tumor toxicity due to low levels of antigen
expression on normal tissue.
In the current project we have modified various
components of our CAR constructs to improve specificity
and overall therapeutic efficacy. Through various
in vitro functional assays and in vivo xenograft models,
we have evaluated and optimized a PSCA-targeting
CAR. We have compared two single-chain variable
fragments with different paratopes, namely the A11 and the
MB1 scFvs. While both show comparable potency, the
MB1 scFv exhibits nonspecific activity against
PSCAnegative tumor lines. Similarly, our data suggest that the
28ζ-costimulatory domain, regardless of linker length,
also shows non-specific activation and killing of
1City of Hope National Medical Center, Duarte, CA, USA
Full list of author information is available at the end of the article
PSCA-negative tumor lines as compared to the 4-1BB
costimulatory domain. Finally, we have demonstrated
differences between long, middle, and short linker
lengths in intracellular cytokine production, activation,
and killing capacities in vitro and in vivo. By modifying
both the ectodomain and intracellular region, we are
able to improve the specificity and functionality of our
PSCA-CARs, which is essential to developing effective
immunotherapies for this advanced disease.
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