In an article published on 30 September 2021 in the Nature Medicine, the researchers of the University of Arizona Cancer Center in Tucson, AZ, US reported the serological and cellular immune responses after two-dose BNT162b2 vaccination of patients with solid tumours on active cytotoxic chemotherapy compared to healthy controls and the outcomes of a phase I study of a third vaccine dose subsequently initiated in the cancer cohort. Together, the data suggest that most patients on active chemotherapy are likely to exhibit improved antibody levels, which has been correlated with protection against COVID-19, after a third immunisation. However, given the relatively modest increases in antibodies and recalcitrance of T cells, expectations should remain tempered as to the degree of benefit. Quantitative antibody tests can potentially be used to select individuals who need and would most benefit from a booster according to the study team.
The authors wrote in the background that several recent reports have shown diminished immune responses to SARS-CoV-2 infections and mRNA vaccines in subsets of immunocompromised patients. In patients with solid or haematological malignancies, antibody responses are markedly diminished after the first immunisation, but improve somewhat after the second. More data are required to determine whether additional immunisations might further protect this vulnerable population.
In this study, the authors compared immune responses to the BNT162b2 mRNA COVID-19 vaccine in 53 patients with solid tumours who were on active cytotoxic therapy to a control cohort of 50 participants without cancer who were enroled through the State of Arizona’s COVID-19 BNT162b2 vaccine point of distribution site at the University of Arizona during the vaccination programme while in the observational waiting area after their first dose.
Neutralising antibodies were detected in 67% of patients with cancer after the first immunisation, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, the study team detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunisations.
To directly determine whether and how immunity can be improved by a third vaccination, the team initiated an interventional study for cancer cohort. From the the original cohort, 20 patients with cancer agreed to participate and met the inclusion criteria. The primary outcome of this phase I study (NCT04936997) of a third BNT162b2 vaccine dose in patients with cancer was immune response, and a secondary outcome was safety.
There were no so obvious demographic differences between the 20 participants and the original cancer cohort; however, these participants had a shorter time between administration of anticancer treatment and blood analyses. Patients in this cohort had gastrointestinal cancers predominantly (75%), compared to 51% in the original cancer cohort; the remaining five participants (25%) had a breast cancer diagnosis, compared to 42% in the original cancer cohort.
At one week after a third immunisation, 16 participants demonstrated a median threefold increase in neutraliszing antibody responses. However, no improvement was observed in T cell responses.
No serious adverse events were noted. Adverse events were mild: 9 participants (45%) experienced injection site pain. Other minor adverse effects included myalgia (15%), bone pain (5%), fatigue (10%), chills (10%) and appetite loss (5%).
The authors wrote that the median age of the cancer cohort was greater than that of controls which raises concerns that some of the differences observed are effects of age rather than of anticancer therapy. When limiting the data to participants older than 39 years, the differences between the two cohorts remained statistically significant for all immunological parameters. These data are consistent with the only modest age-dependent effects in immune responses reported in BNT162b2 phase I clinical studies.
The authors commented about age-moderated effect within the control group in terms of anti-RBD titres. However, no other immunological parameters were similarly affected, and they did not observe age-moderated effects within the cancer cohort for any immunological parameter. Thus, the major driver of diminished responses in the cancer cohort is likely to be anticancer therapy rather than age.
The study team observed lower overall antibody and T cell responses in patients with cancer compared to control cohorts. However, it is encouraging that they also observed T cell responses in most vaccinated patients with cancer, including nearly half who mounted undetectable neutralising antibody responses. Unlike antibodies, these T cell responses were only modestly reduced relative to the control cohort. The authors concluded that their results suggest that a third dose of BNT162b2 is safe, improves humoural immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy.
Reference
Shroff RT, Chalasani P, Wei R, et al. Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors. Nature Medicine; Published online 30 September 2021. https://doi.org/10.1038/s41591-021-01542-z