Oncotarget: Evaluations in the TRAMP prostate cancer model

Oncotarget recently published "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model" which reported that the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer.

CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals.

In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable.

Combination of CRC2631 with checkpoint blockade reduces metastasis burden.

Collectively, these Oncotarget findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Collectively, these Oncotarget findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies

Dr. Yves C. Chabu from The University of Missouri said, "Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities."

Figure 5: CRC2631/PD1 blockade combination treatment reduces metastatic burden. (A) Graph showing percentage change of ventral prostate tumor volume in 8–10-week-old B6FVB TRAMP (+) animals (N = 12) following IV treatment with PBS [no treatment (NT)] or 2.5 × 10⁷ CRC2631. Animals received a single dose of indicated treatment every three days for a total of 4 injections. Tumor volume was determined using the volumetric image analysis platform IMARIS BITPLANE and MRI images taken 5–7 days before and 21 days after treatment. (B) Box plot showing gene expression change in Transcript Per Million on a log2 scale (TPM+1, N = 3) in PC3M and PC3 human prostate cancer cell lines before and after treatment with CRC2631. NT = No Treatment, 2631 = CRC2631 treated cells. (C and D) Flow cytometric profiling of tumor-infiltrating lymphocytes (TIL) in metastasized lymph nodes extracted from PBS [no treatment (NT)] or CRC2631-treated B6FVB TRAMP (+) animals. Cells were sorted on CD3, CD69, CD4 (C), and CD3, CD4, PD1 (D). Graph depicts the frequency of the indicated TIL phenotype across groups. P-values are derived from students' t-test analyses. (E) Enumeration of metastases observed in lymph nodes and lung tissues from MRI images taken 21 days after treatment from groups of 8–10 weeks old B6FVB TRAMP (+) animals (N = 12) treated (IV) with PBS or 2.5 × 10⁷ CFU of CRC2631 or 0.5 mg of a murine anti-mouse PDL1 antibody (Invivomab), or a combination of CRC2631 (2.5 × 10⁷ CFU) and Invivomab (0.5 mg). Animals in each group received a single dose of the indicated treatment every three days for a total of four injections. P-values denote student t-test significance. (F–K) Representative in vivo MRI images of B6FVB TRAMP (+) mice 21 days after start of CRC2631+Invivomab treatment (H and K) compared to PBS control group (F–G and I–J). Red arrows: lung metastasis; green arrows: lymph node metastasis. L: lungs; Li: liver; K: kidney.

Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains.

VNP20009 was first isolated in a genetic screen for hyper invasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028.

CRC2631 was derived from a parent strain that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain.

This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains.

Similar to prostate cancers in men, these murine carcinomas disseminate throughout visceral organs, differentiate into neuroendocrine prostate cancer, and ultimately kill the host.

The Chabu Research Team concluded in their Oncotarget Research Paper, "Importantly, CRC2631 reduced metastasis incidence in the setting of checkpoint blockade. This is significant because metastasis is the main cause of cancer-associated deaths and no effective immunotherapy against prostate cancer currently exist."

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DOI - https://doi.org/10.18632/oncotarget.27769

Full text - https://www.oncotarget.com/article/27769/text/

Correspondence to - Yves C. Chabu - chabuc@missouri.edu

Keywords - salmonella, cancer targeting, prostate cancer, immunotherapy, TRAMP

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