The extensive deployment of COVID-19 vaccination has raised new concerns about clinical interactions between active antiviral immunization and immunologic therapies [17]. Since the third dose of tozinameran is expected to maximize the humoral and cellular immune responses [18–19], its impact on cancer patients receiving ICI-based treatments warrants special attention. In this research, we investigated the specific safety and disease outcomes of patients treated with ICIs for a wide range of advanced solid malignancies over a six-month period following booster dosing. Although longitudinal assessment of humoral responses confirmed a significant increase in antibody titers after the third dose, we observed no difference in the frequency of irAEs. However, it is noteworthy that recipients who demonstrated a more sustained antibody response had a significantly higher incidence of moderate to severe immune-related thyroiditis. The same patients also appear to benefit from improved time-to-event outcomes as a result of a lower risk of loss of disease control and death. The fact that, to the best of our knowledge, similar findings have not been previously reported requires a critical assessment of their clinical relevance.
Because COVID-19 vaccination might elicit hyperstimulation of T-cell and dendritic cell functions [20] and increased cytokine release [21], concomitant treatment with ICIs has been considered a risk factor for developing severe irAE. After initial evidence of a favorable short-term safety profile in this group of patients [11], a subsequent prospective study confirmed a low rate of severe irAEs in mRNA-1273 vaccine recipients receiving ICIs with or without cytotoxic chemotherapy [22]. Our prospective assessment indicates an incidence of any grade immune-related toxicities within the expected range [23], with no increase after the booster dose of the vaccine. In addition, the median time to irAE development and lack of exacerbation of previous toxicities is consistent with the results of two retrospective series addressing these aspects of ICI treatment after the second dose [24–25]. The apparent increase in the frequency of thyroiditis was relatively unexpected because it has already been described as an autoimmune disorder associated with SARS-CoV-2 vaccination [26]. In contrast to what has been described in noncancer patients, we observed a significant association with antibody response magnitude, which might suggest a direct interaction between vaccination and ICI therapy [27].
The clinical effects of SARS-CoV-2 vaccination on the efficacy of ICI-based therapies are currently unknown. However, the complex relationship between vaccine adaptive responses and immune checkpoint blockade has raised concerns about a potential increase in tumor hyper-progression [28]. This paradoxical phenomenon has been related to diffuse infiltration of metastatic sites by activated lymphocytes as a result of enhanced effects of the vaccination itself [29]. In this regard, two retrospective studies reported that influenza vaccination could even provide an advantage in terms of overall survival, ruling out the generic risk of hyper-progression associated with active antiviral immunization during ICI exposure [30–31]. Nonetheless, because COVID-19 vaccination may elicit a more intense and less predictable immune response than influenza vaccines, the threat of a detrimental effect on disease outcome cannot be overlooked. A large retrospective study showed that the clinical benefit of the anti-PD-1 agent camrelizumab has similarly improved in the subgroup of patients who received the SARS-CoV-2 BBIPB-CorV vaccine compared with their unvaccinated counterpart [32]. Despite significant differences in methodology, our results appear to be consistent with the described evidence, implying that COVID-19 vaccination does not reduce the clinical efficacy of ICI treatment. Similar to previous studies, we did not observe any case of hyper-progression, nor did the rate of loss of disease control differ from what was expected before the third dose of tozinameran. Although the unavoidability of SARS-CoV-2 vaccination during COVID-19 outbreaks precluded a direct comparison with unvaccinated patients, we observed a significant survival advantage in favor of high-level responders, which seems to further support previous suggestions.
The current study acknowledges several shortcomings, including but not limited to the following issues. The Vax-On-Third, like all others of its kind, was designed to enroll large numbers of patients in a short time frame. While the need to address COVID-19-related emergency may explain such an approach, this "all-comers" recruitment did not allow for adequate stratification of participants, making the study prone to selection bias. We included a wide variety of malignancies, implying that different interactions between vaccination and ICIs cannot be ruled out among patients with different types of cancer. The specific design of the present research also has inherent immortal-time bias, which results from the lapse between initiation of ICI treatment and vaccination, potentially leading to an overestimate of the survival benefit [33]. The lack of a linear correlation between antibody titers and duration of overall survival, which has otherwise been reported for time-to-treatment failure, is consistent with the latter consideration. In addition, we did not provide an independent radiological review or immune-related evaluation of treatment response [34]. These flaws may have led to an incorrect assessment of ICI activity and V-TTF duration. Finally, despite being overlapped with those of similar studies, the sample size of this series is small, as is the median duration of follow-up, which is relatively short. The last issues emphasize that multivariable statistical comparisons may amplify false-positive results, the significance of which should be therefore considered exploratory.
In conclusion, many areas of uncertainty remain in cancer patients receiving ICIs with regard to the third dose of COVID-19 vaccination. We investigated the effects of antibody response in this condition for the first time. Our results suggest a favorable clinical interaction, resulting in improved disease outcomes without an overall increase in immune-related toxicities. These results would strengthen the recommendation that immunotherapy plans not be changed based on immunization schedules [35]. The increased incidence of specific adverse events associated with both vaccination and treatment, including autoimmune thyroiditis, implies that all these patients should be closely monitored. The limitations of the study and the lack of reliable comparisons indicate that these results have hypothesis-generating potential, which should be confirmed in independent prospective cohorts.