Blood cancer: Third COVID-19 vaccination improves immune response


New research has found that the weakened immune systems of blood cancer patients can improve after they receive a third COVID-19 vaccination.

Patients with lymphoma have defects in their immunity system that restrict its response to vaccination. Despite this, this new study found improvements in antibody and T-Cell responses after a third vaccine dose, except in patients who had recently received a certain antibody treatment for their cancer.

The study was funded by the Blood Cancer UK Vaccine Research Collaborative and has been published in the journal Nature Cancer.

“Despite the gradual lifting of COVID-19 restrictions worldwide, a cloud continues to hang over immunosuppressed patients, who may not develop protective immune responses after vaccination,” explained Dr. Sean Lim, Associate Professor and Honorary Consultant in Haematological Oncology at the University of Southampton, who led the research.

“In particular, individuals with hematological malignancies are at greater risk of severe COVID-19 disease even if they have been vaccinated,” she continued.

Dr. Lim and her team collected blood samples from 457 adult lymphoma patients before they received their first vaccination of either the Oxford-AstraZeneca or BioNTech Pfizer vaccines, and four weeks after the first dose, two to four weeks and 6 months after the second dose, and four to eight weeks after the third dose.

The study aimed to evaluate the strength of the immune system’s response to the vaccines and to help predict how effective the vaccine could be for lymphoma patients.

To achieve this, the scientists measured the ability of antibodies in the blood samples to prevent the viral spike protein from binding to ACE2 proteins, which are the virus’s key point of entry into the human body. They also measured the response of T cells—which form part of the body’s immune system – when stimulated by the viral spike.

The results showed that whilst just over half of patients undergoing active cancer treatment had no detectable antibody levels after the second vaccination, T cell responses could be detected in about two thirds of all patients. After a third dose, 92 percent of patients who were not undergoing anti-CD20 treatment for their cancer showed improved antibody responses, compared to 17% who were receiving that treatment.

“We observed a good link between the level of antibodies in the blood samples and how well these antibodies blocked the virus from binding to the ACE2 protein,” said Dr. Lim. “This suggests that the antibodies induced in patients with lymphoma perform similarly to those in healthy donors.”

A key question for patients with suppressed immunity systems is whether there is a connection between antibody and cellular responses and the risk of infection, hospitalization and death from COVID-19. The research team will therefore follow up this research with further analysis into the clinical outcomes of patients in this study who were infected with COVID-19.

Vaccines against COVID-19 are a promising approach to prevent and mitigate COVID-19. Overall, systemic reactogenicity events have been reported by 50% and 69% of patients after the first and second doses of RNA-based COVID-19 vaccines, respectively.1 These events, such as fever, headache, myalgias, and chills, are direct manifestations of the innate immune response to vaccination that results in the production and release of pyrogenic cytokines and inflammatory mediators, activation of complement, and recruitment of immune cells.2

Interestingly, spontaneous tumor regression following an intense immune-inflammatory response, usually triggered by a pathogen infection, has been recognized for centuries and guided the first steps toward immunomodulation of the microenvironment to treat cancer. The first reported immunotherapy against cancer was the inoculation of streptococcal organism into patients with unresectable sarcomas,3 and for over three decades, administration of the BCG vaccine to promote local inflammation has been used to treat non-muscle-invasive bladder cancer.

Here, we describe dramatic tumor regression in a patient with metastatic myoepithelial carcinoma of the parotid who experienced intense reactogenicity following the second dose of the mRNA-1273 COVID-19 vaccine.

Severe hyperinflammatory response occurs in a fraction of patients with COVID-19.7 Similarly, COVID-19 vaccines have the potential to evoke intense immunologic responses.8 Here, we describe a case of an anticancer response after COVID-19 vaccination. Histology analysis and tumor molecular profiling suggested that the primary tumor was poorly immunogenic, which is associated with poor responses to the most commonly used cancer immunotherapy.

Notably, the patient reported grade 3 systemic adverse events after the second dose of the COVID-19 vaccine, which was preceded by spontaneous tumor regression, indicating that an intense inflammatory host response stimulated by the vaccine may have promoted an antitumor response.

The changes we observed in the TIME between the prevaccination and postvaccination tumor specimens, including increases in CD8+ and CD4+ T cell tumor infiltration and granzyme B+ cytolytic cells, are associated with immune cell activation. Moreover, we found notable reduction in the absolute number of tumor cells and the fraction of remaining cells actively proliferating, indicating an effective anti-cancer response, consistent with the patient’s radiological findings.

CD8+ cytotoxic T cells have a pivotal role in the anti-cancer immune response; in fact, enhancing their activity is the main strategy of current successful cancer immunotherapies. Interestingly, although the efficacy of most vaccines is largely related to induction of antibody responses, T-cell-mediated immunity has emerged as an important mechanism of host defense against severe respiratory syndrome coronavirus-29; COVID-19 vaccine has been shown to induce both virus-specific antibodies and T-cell responses,9 which align with the TIME changes found in our analysis.

Dendritic cells, macrophages, and B cells are major populations of antigen-presenting cells critical for the initiation of adaptive immune response through T-cell activation, which is crucial for both vaccine-induced and anti-cancer immunity. Our finding of a substantial increase in antigen-presenting cell tumor infiltration in postvaccination samples is consistent with the robust innate and adaptative anticancer responses experienced by this patient.

Notably, we observed a shift in the TIME composition from myeloid predominant to lymphocytic predominant. Fractions of immune suppressive cells, represented by M2-macrophages, regulatory T cells, and cancer-associated fibroblasts, were higher in prevaccination samples than in postvaccination samples, which align with previous literature showing that immune suppressive cells are associated with immune evasion and worse prognosis in cancer.10

Finally, dysfunctional and exhausted T cells, represented by expression for TIM3,6 were also more prevalent in the pre-vaccination samples, whereas TIGIT expression in T cells was higher after vaccination and may be associated with T-cell activation.

In summary, this patient’s clinical course and the analysis of prevaccination and postvaccination tumor samples support the hypothesis that stimulation of the innate immune system by the mRNA-1273 COVID-19 vaccine induced systemic immune activation and led to a robust and persistent anticancer response, represented by radiological tumor shrinkage and an ‘anticancer’ TIME composition.

To our knowledge, this is the first reported case of COVID-19 vaccine-induced tumor regression and the first report of spontaneous tumor regression in a patient with salivary myoepithelial carcinoma. Host and tumor characteristics that led to this phenomenon remain unclear.

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More information: Sean H. Lim et al, Immune responses against SARS-CoV-2 variants after two and three doses of vaccine in B-cell malignancies: UK PROSECO study, Nature Cancer (2022). DOI: 10.1038/s43018-022-00364-3



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