Integrating Cancer Vaccines in the Standard-of-Care of Ovarian Cancer: Translating Preclinical Models to Human

Chiang, Cheryl Lai-Lai; Rovelli, Raphaël; Sarivalasis, Apostolos; Kandalaft, Lana E.

doi:10.3390/cancers13184553

Cited by 9 publications

(2 citation statements)

References 172 publications

(191 reference statements)

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“…Combination with oncolytic viruses for induction of innate and natural killer cell responses 47 48 and vaccines that elicit endogenous T-cell activity could be key combination therapies to sustain tumor control, without the emergence of CAR-antigen loss variants. [49][50][51][52] There is some evidence that endogenous T cells can be recruited in the ID8 tumor model, 50 53 but their existence in the ID8 CAR system described here remains to be seen. Nevertheless, our findings using a single dose of CAR T-cells are even more notable given that other strategies would likely provide greater benefit through synthetic engineering, recipient T cell selections, or combination treatments.…”

Section: Discussionmentioning

confidence: 88%

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model

Rañoa

Sharma

Schane

et al. 2023

J Immunother Cancer

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BackgroundTreatment of some blood cancers with T cells that express a chimeric antigen receptor (CAR) against CD19 have shown remarkable results. In contrast, CAR-T cell efficacy against solid tumors has been difficult to achieve.MethodsTo examine the potential of CAR-T cell treatments against ovarian cancers, we used the mouse ovarian cancer cell line ID8 in an intraperitoneal model that exhibits disseminated solid tumors in female C57BL/6J mice. The CAR contained a single-chain Fv from antibody 237 which recognizes a Tn-glycopeptide-antigen expressed by ID8 due to aberrant O-linked glycosylation in the absence of the transferase-dependent chaperoneCosmc. The efficacy of four Tn-dependent CARs with varying affinity to Tn antigen, and each containing CD28/CD3ζ cytoplasmic domains, were compared in vitro and in vivo in this study.ResultsIn line with many observations about the impact of aberrant O-linked glycosylation, the ID8Cosmcknock-out (ID8Cosmc-KO) exhibited more rapid tumor progression compared with wild-type ID8. Despite the enhanced tumor growth in vivo, 237 CAR and a mutant with 30-fold higher affinity, but not CARs with lower affinity, controlled advanced ID8Cosmc-KO tumors. Tumor regression could be achieved with a single intravenous dose of the CARs, but intraperitoneal administration was even more effective. The CAR-T cells persisted over a period of months, allowing CAR-treated mice to delay tumor growth in a re-challenge setting. The most effective CARs exhibited the highest affinity for antigen. Antitumor effects observed in vivo were associated with increased numbers of T cells and macrophages, and higher levels of cleaved caspase-3, in the tumor microenvironment. Notably, the least therapeutically effective CAR mediated tonic signaling leading to antigen-independent cytokine expression and it had higher levels of the immunosuppressive cytokine interleukin10.ConclusionThe findings support the development of affinity-optimized CAR-T cells as a potential treatment for established ovarian cancer, with the most effective CARs mediating a distinct pattern of inflammatory cytokine release in vitro. Importantly, the most potent Tn-dependent CAR-T cells showed no evidence of toxicity in tumor-bearing mice in a syngeneic, immunocompetent system.

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Section: Discussionmentioning

confidence: 88%

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model

Rañoa

Sharma

Schane

et al. 2023

J Immunother Cancer

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“…Immunotherapy for the treatment of ovarian cancer remains controversial ( 2 ). Early observations that intratumoral T-cell infiltration is associated with better survival led to the hypothesis that ovarian cancer is immunogenic and potentially responsive to immunotherapy ( 3 ). Challenging this hypothesis is a recent observation that the tumor mutational burden, which correlates with the number of neoantigens, is in the lower end of spectrum for ovarian cancer with only 1–3.5 mutations/Mb (immunogenic melanoma has 14–47 mutations/Mb).…”

Section: Introductionmentioning

confidence: 99%

Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer

Kos,

Frankel,

Cristea

et al. 2023

Cancer Research Communications

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Purpose: Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment. Experimental Design: Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression. Results: We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7–3.8) and median overall survival was 15.1 months (9.4–30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells. Conclusions: p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab. Significance: The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

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Immunotherapy for HPV negative head and neck squamous cell carcinoma

Jiang,

Elkashif,

Coulter

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Integrating Cancer Vaccines in the Standard-of-Care of Ovarian Cancer: Translating Preclinical Models to Human

Cited by 9 publications

References 172 publications

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model

Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer

Immunotherapy for HPV negative head and neck squamous cell carcinoma

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