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Microbes & Immunity Factors associated with response to T-VEC

were receiving concurrent immunotherapy treatment, yet This study is limited by a small sample size of 18 patients,
we did not observe an improvement in clinical outcomes which restricts the ability to identify statistically significant
with concurrent therapy. However, multiple studies have covariates associated with the response to T-VEC treatment
demonstrated the efficacy of T-VEC even after failure of and precludes multivariate analysis to assess for cofounders.
immunotherapy. 6,24,25 Our findings are consistent with this This limitation is evident in the inconsistencies between
observation, as we observed salvage in patients who had our Fisher’s exact test and continuous t-test analysis and
recurred or progressed after or during ICI. the Kaplan–Meier analysis. Our statistical approach was
The optimal timing for sequencing or combining chosen to best accommodate the small sample size and
treatments is concurrently unclear. However, our findings low numbers of recurrence events and deaths. Despite this
indicate that increasing lines of prior systemic therapy limitation, our observations suggest that further analysis
and ICI are associated with poorer outcomes, suggesting in larger, ideally multicenter, populations is warranted. As
that failure of prior lines may be indicative of resistance this is a single-center clinical cohort, there can certainly be
to oncolytic viral therapy as well. Patients who have implications regarding patient selection and administration
experienced failure on multiple lines of therapy may techniques. All our T-VEC administrators were physicians
also have a higher disease burden, although further trained and certified in ultrasound, though there have not
investigation with a larger cohort study would be necessary been any trials or formal analyses examining how technical
to validate this correlation. Moreover, prior lines of therapy aspects of administration might impact outcomes. Finally,
may selectively foster the emergence of cell populations our patient population was 100% Caucasian, which,
with heightened resistance to therapies. Therefore, while reflecting the population in Vermont and upstate
integrating T-VEC earlier in the treatment course could New York, may limit the generalizability of our analysis to
prove efficacious, either through concurrent treatment or patients of different racial backgrounds.
as salvage therapy after initial immunotherapy failure. 5. Conclusion
A phase 2 trial demonstrated promise for reducing
recurrence-free survival with the use of neoadjuvant Despite a small sample size, our study demonstrated
T-VEC. Ongoing neoadjuvant trials may inform the statistically significant results, such as an improved ORR in
10
timing for incorporating T-VEC early into therapy and patients with lower-burden disease and worse DFFS with
provide opportunities to study biological markers of higher lines of prior systemic therapy. The ability to salvage
response. Dummer et al. found that increased CD8+ patients after prior ICI, but the worsening outcomes
10
density correlated with clinical outcomes in their following increasing lines of ICI and systemic therapy,
exploratory analysis. This finding, along with our clinical suggests that oncolytic treatment might be more effective if
finding that patients who experienced a bystander response considered earlier in therapy. It also indicates that multiple
demonstrated improved DDFS and OS, suggests that prior failures of ICI may predict a decreased response
the ability of T-VEC to elicit an immune-based response to herpes-directed oncolytic treatment. In addition, we
beyond its direct oncolytic activity is important for clinical observed several other covariates demonstrating trends
outcomes beyond the in-field ORR. Given the strong toward significance, warranting further studies with a
signal of benefit, despite the limited number of patients larger population.
who could be evaluated for bystander response (50% of
our patients had uninjected lesions), this subset of patients Acknowledgments
would be of interest for future studies. These studies None.
should include biomarker analyses for patient selection
and ways to optimize the immune-based component of Funding
the treatment effect. A bystander response may reflect None.
patients with a stronger immune-enhancing response,
suggesting that the immune-enhancing component (rather Conflict of interest
than the cytolytic component) may be more significant for
determining clinical outcomes. Given that in-field ORR The authors declare that they have no competing interests.
was not associated with OS, this suggests an important Author contributions
distinction in the type of response and its impact on
survival outcomes. Research to identify biological factors Conceptualization: Anupama Balasubramanian, Michela
related to the tumor, microenvironment, and mechanisms Salusti-Simpson, Conor O’Neill, Mirabelle Sajisevi,
of resistance is ongoing to improve patient selection Jessica Cintolo-Gonzalez
process. 26-30 Investigation: Anupama Balasubramanian, Michela Salusti-

Volume 1 Issue 1 (2024) 103 doi: 10.36922/mi.3445