Muhammad Bilal Abid, MD, MRCP

Patients who undergo hematopoietic cell transplantation (HCT) or receive cellular therapies have been shown to have suboptimal outcomes after COVID-19 infection. Poor serological response to the initial 2-dose SARS-CoV-2 mRNA vaccine series has prompted investigators to assess the effect a third dose may have in improving outcomes for this population.

In a study published in Cancer Cell,¹ investigators evaluated 75 patients treated with allogenic HCT (n = 30), autologous HCT (n = 26), chimeric antigen receptor (CAR) T-cell therapy (n = 10), or bispecific T-cell engagers (n = 9; BiTEs) who did not seroconvert after their primary vaccination series. Following a third dose of a SARS-CoV-2 mRNA vaccine, 59% developed antibodies against COVID-19. The seroconversion rates were 58%, 63%, 40%, and 67%, respectively. No significant differences were reported between vaccination with the approved vaccines BNT162b2, mRNA1273, or mix-and-match.

In an interview with OncLive^®, Muhammad Bilal Abid, MD, MRCP, a coauthor of the study, discussed the rationale of the study and clinical takeaways regarding the standard use of a third SARS-CoV-2 mRNA vaccine dose among patients treated with HCT, CAR T-cell therapy, and BiTEs. Abid is an assistant professor of medicine in the Divisions of Hematology/Oncology and Infectious Diseases at the Medical College of Wisconsin in Milwaukee.

OncLive^®: What is known about transplant and cell therapy recipients and their outcomes after infection with COVID-19?

Abid: By now we know that when transplant recipients, particularly HCT recipients and CAR T-cell recipients, develop COVID-19, they have pretty poor outcomes. In the large [Center for International Blood and Marrow Transplant Research] CIBMTR analysis that included 318 patients, we showed a mortality rate of [approximately] 30% at 30 days after HCT recipients developed COVID-19.²

Another similarly designed registry analysis by the European Blood and Marrow Transplant Registry that included 56 CAR T-cell recipients, who predominantly received CD19, showed that all adults, except for 1 child, also had a fairly high COVID-19-attributable mortality rate that exceeded nearly 41% at 30 days.³

What inspired your team’s analysis of serological responses to a third vaccine dose in this population?

This subset of immunocompromised patients do not mount an adequate immune response to SARS-CoV-2 vaccines, particularly a humoral immune response. We have to resort to certain novel strategies in parallel [to vaccination].

Over the past few months, we [have seen] in the general population that waning immunity can be counteracted with an additional dose of a SARs-CoV-2 vaccine. That was the first thing that we wanted to explore—a third dose of an mRNA-based vaccine. We are looking at several ways of how we can improve immune response in this patient subset, and this was the first avenue we wanted to explore

Please describe the methods used for the research.

With this background in mind, we designed this study with fairly strict inclusion and exclusion criteria and examined serological responses to a third mRNA vaccine dose, primarily to the BNT162b2 and mRNA-1273 vaccines. The key inclusion criteria was that all patients did not seroconvert to any degree after receiving the 2-dose primary vaccination series.

Patients had their immune responses checked after 2 doses, as well as after the third dose. [We also ensured patients] had enough time between the second and the third dose [28 days] as well as between the third dose and a humoral response assessment [14 days] to be able to mount a response based on their delayed immune reconstitution.

We excluded those patients who had developed COVID-19 any time prior to the third dose, just to be homogenous. For detection of antibodies at all time points, we used a single validated immunoassay that detected an IgG directed against the receptor binding domain of the S1 subunit of the spike protein of the virus.

What would you say were the key findings from your research? Did you find any of them particularly surprising?

With these inclusion and exclusion criteria, we put together a cohort of 75 patients that included 30 autologous recipients, 26 allogeneic recipients, 10 CAR T-cell recipients, and 9 BiTE recipients. All [those treated with BiTEs] were patients with myeloma, predominantly treated with BCMA-directed BiTEs and a handful treated with GPRC-directed BiTEs.

I want to reiterate that all 75 of these patients had not seroconverted to any degree after receiving 2 doses of the initial primary vaccination series. Fifty-nine percent of patients developed protective antibodies after the third dose. When stratified by subgroups, the seroconversion rates were 63% among autologous transplantation recipients, 58% among allogeneic transplantation recipients, 40% among CAR T-cell recipients, which was the lowest seroconversion rate, and 67% among myeloma BiTE recipients.

[Although] we found no significant differences in seroconversion rates based on contemporary relevant clinical variables, corticosteroid usage stood out both in terms of seroconversion rates and median IgG antispike titers, post third dose. There was a significant difference between the titers among those patients who were receiving any dose of corticosteroids at the time of third dose vs those who were not.

On subgroup analysis, we also noted a significant difference in seroconversion rates between [patients with] myeloma and lymphoma. In the autologous transplant subgroup, [patients with] myeloma seroconverted better than patients with lymphoma.

A couple of findings that were surprising to our group were that we looked at gender in a binary manner—the data limited us and really forced us to do that—and [though] they were no significant differences in seroconversion rates between men and women, the median titers after a third those were significantly higher among females [compared with] males. The other surprising finding was that although seroconversion rates were decent among BiTE recipients after the third dose, median antispike titers were actually fairly low among myeloma BiTE recipients. We believe that these findings are hypothesis generating and will lead to further studies.

How would you say these findings fit with other studies that have examined vaccine doses in transplant recipients?

The data on the efficacy and safety of a third of dose in this subgroup of patients are fairly limited. Three other studies so far have reported data with a third dose in an allogeneic transplant recipient [population]. [Investigators of] one study looked at 70 patients, another study looked at 42 patients, and a third study looked at 38 patients. [These studies] examined response to accumulative 3 doses that, not to just a third dose. [Results were] fairly consistent, [investigators of] 1 [study] reported a seroconversion rate of 41% and another was similar. The study that looked at 38 patients cumulatively after 3 doses reported a response rate of 87%. [We concluded] that a third dose is something which is very important for this subgroup of patients.

Expanding a little bit on what was found with regard to CAR T-cell recipients, what would you say are some of the factors that are indigenous to this population that may have accounted for blunted responses to vaccines?

Continued blunted responses are concerning among [patients who receive] CAR T-cell therapies. They are certainly an incongruence with other reported literature. Recipients of CAR T-cell therapy are profoundly immunosuppressed, by the time they get the CAR T-cell therapy primarily because of their underlying disease being so refractory.

By the time they get to CAR T-cell therapy, patients are not maintaining good performance status. Factors related to this include the underlying CAR T construct, signaling domain, the antigen that it targets, the severity and duration of cytokine release syndrome, and immunomodulators that are used to counteract these early on-target, off-tumor toxicities. Some of the other collateral damage that comes along with CAR T-cell therapy, such as prolonged B-cell aplasia, prolonged cytopenia are some of the factors that are driving these continued and consistently blunted immune responses in [patients who have received] CAR T-cell therapies.

Are there any approaches being explored to overcome some of these challenges faced with getting responses in these patients?

First and foremost, mitigation strategies [such as] the vaccination of all health care providers caring for this group of patients. Caregivers involved should be completely vaccinated with a booster dose.

A third dose for the patients themselves is also imperative and an additional fourth dose is now recommended by the CDC, per the revised guidelines, at least 3 months out from the third dose. Novel strategies such as early usage of broadly acting monoclonal antibodies that are approved for usage in either the prophylactic setting and a preexposure setting, or to prevent the progression of COVID-19 from mild to moderate, or severe illness could certainly be used earlier in patients who are at a higher risk of a diminished response or no responses to any dose of vaccines.

What were the top takeaways from the data readout for patients who received BiTEs?

In terms of BiTE recipients, there are really no data on vaccine responses. There are very small studies, 1 or 2 at the most. It is early and premature. [Patients with] multiple myeloma who are receiving BiTEs are relapsed or refractory [and] with each subsequent relapse the disease biology changes, accumulation of mutations occur, and patient performance status declines.

There is so much going on and then BiTEs come in and target specific tumor antigens and deplete normal cells that also bear those antigens[ and] there is a certain degree of collateral damage. At this point in time, it would be premature to comment on that. As a greater body of data evolves, we would be in a better position to comment on some of the mechanisms that underlay blunted immune responses.

Are there any limitations to this analysis that should be noted?

There are limitations to our study that are indigenous to the retrospective design of the study. We were limited by the data we had; we did not have serial assessment of humoral response at predefined time points. We did not capture any cellular immune responses, which are equally as important as the antibody responses.

In terms of the latest variant of concern, the B.1.1.529 omicron variant, which we luckily are almost over with at this point, we can’t comment on protection with a third dose. [This is] primarily because our cohort included 8 patients who were treated either after or around November 26, 2021, the time at which the World Health Organization declared the omicron variant as a variant of concern.

Are there any next steps to this research? Are there any open questions that you would like to see answered?

We need to see the efficacy and safety data of monoclonal antibodies: sotrovimab [Xevudy] and Evusheld [tixagevimab and cilgavimab] in the preexposure setting for the prevention of progression of illness. That’s something that’s worth exploration.

[We also would like to see data on] a fourth dose among the subset that do not seroconvert or have low responses after 3 doses is also worth exploration. There are large prospective studies that are ongoing, such as a large CIBMTR BMT CTN [The Blood and Marrow Transplant Clinical Trials Network] study [the] interim analysis results [of which] will be presented at the American Society of Transplantation Cellular Therapy meeting in late April in Salt Lake City. We are keenly looking forward to those results.

What would you say your colleagues should take away from this research?

The big takeaway from our study is that a third dose works. A third dose should be considered for every transplant, CAR T-cell therapy, and BiTE recipient, as often as possible.

For patients who do not respond to a third dose, a subset of patients will benefit from the reassessment of antibodies. If a third dose does not work, go for a fourth dose [and] this should be discussed with an infectious disease colleague at the center. There is a multidisciplinary collaborative approach that we have to provide.

Talk to your clinical trials office and keep talking to your industry partner [and] see if you can [have] some [access to] antibody usage going in this subset of patients, even off label. At the end of the day, we are all clinicians and the patient’s best interest is first and foremost.

References

1. Abid MB, Rubin M, Ledeboer N, et al. Efficacy of a third SARS-CoV-2 mRNA vaccine dose among hematopoietic cell transplantation, CAR T cell, and BiTE recipients. Cancer Cell. Published online February 23, 2022. doi:10.1016/j.ccell.2022.02.010
2. Sharma A, Bhatt NS, St Martin A, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e193. doi:10.1016/S2352-3026(20)30429-4
3. Ljungman P, de la Camara R, Mikulska M, et al. COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey. Leukemia. 2021;35(10):2885-2894. doi:10.1038/s41375-021-01302-5