Efforts Needed to Evaluate How CAR T-Cell Therapy Recipients Respond to COVID-19 Vaccination

Muhammad Bilal Abid, MD

Although CAR T-cell therapy have resulted in unprecedented response rates in patients with hematologic malignancies, the modality comes with distinctive toxicities and infection risks that may impact the effectiveness of COVID-19 vaccines, according to Muhammad Bilal Abid, MD, who added that more data are needed to better understand how to protect this vulnerable population amidst the pandemic.

In a recent review paper, Abid and colleagues delved into the state of CAR T-cell therapies and determinants of responses to SARS-CoV-2 vaccines.¹ Available data indicate that the risk of infections with CAR T-cell therapies depend on several patient- and disease-related factors, as well as the CAR T-cell constructs and targets themselves. Findings associated with COVID-19 outcomes and vaccine responses in this population continue to evolve.

“No matter how durable a CAR T is, if your CAR T-cell recipient develops COVID-19, their mortality risk is high,” Abid said. “This is known from data that have been gathered so far and is not the best. As such, it is important to protect them from contracting [the virus].”

In an interview with OncLive^®, Abid, assistant professor, Hematology, Infectious Disease, Internal Medicine, Medical Oncology, Medical College of Wisconsin, discusses immune-compromising factors that are indigenous to CAR T-cell recipients, the immunogenic potential of different vaccines, determinants of response, and the potential need for booster strategies.

OncLive^®: Could you provide a snapshot of some of the progress that has been made with CAR T-cell therapies in hematologic malignancies? What are some of the challenges faced with this modality, and what inspired this review paper?

Abid: Considerable progress has been made in the CAR T-cell therapy arena over the past decade. The focus has primarily been on improving the durability of CAR T-cell therapy, and every new construct is more sophisticated, and more advanced than the last, in terms of harnessing newer costimulatory domains to render a greater level of durability in the next generation [of products].

Moreover, the more durable a CAR T-cell therapy becomes, the more prolonged the long-term, off-tumor toxicities become. Although many [toxicities] have been discussed, such as cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS], other toxicities like B-cell aplasia, prolonged hypogammaglobulinemia, and prolonged cytopenia, have not been explored as much.

As more of these CAR T-cell therapies become available, and they start to move toward the frontline setting, it is important to determine how to keep patients safe from infections that occur because of the prolonged adverse effects [AEs] associated with these treatments.

You mentioned the importance of being aware of the toxicities associated with this modality. What are some of the factors that predispose patients to infections or poor outcomes with these therapies? What is known thus far about the varying toxicities observed between the different constructs and targets?

We can broadly classify these factors into 3 categories: determinants that are indigenous to the CAR T-cell construct, those that are patient related, and those that are disease related.

The patient-related factors are conventional; they include a poor performance status or a higher comorbidity burden. The disease factors are also pretty standard, and include whether the disease is in remission; this is unlikely, as most patients who receive CAR T-cell therapy do not have controlled disease.

The key determinants associated with the CAR T-cell therapy itself are indigenous to the CAR T construct. [We need to know] what happens right before or after CAR T-cell therapy. [We need to know] the dose or the intensity level of lymphodepletion chemotherapy [received prior to CAR T-cell therapy]. A higher dose creates a good immune milieu to allow CAR T-cell persistence, but it may also predispose patients to prolonged cytopenia or grade 4 neutropenia and thrombocytopenia for a prolonged duration.

Bridging therapy is also important to mention, although the role of this is unclear. Patients who need bridging therapy may do poorly at the end; however, these [patients typically have] aggressive disease and they eventually rapidly progress. The other school of thought is, if patients need bridging therapy, that means the disease will [require] a certain level of control prior to CAR T. What happens between cell collection and CAR T-cell infusion is important.

With CAR T constructs themselves, whether it is 4-1BB based or it’s CD28 based, indigenously, these signaling domains have rapidity of T-cell impact. With CD28, it comes at you; there is more CRS, more rapid onset of CRS, a higher degree of CRS, and higher severity CRS. 4-1BB is slower and so the degree of CRS is [not as severe]. No prospective studies have compared these 2 constructs head-to-head. However, preclinical data [have indicated that] CD28 confers a higher degree of CRS vs 4-1BB. 4-1BB is associated with higher durability, although prospective data are needed.

CRS has been shown, multiple times, to be an independent risk factor and a driver of infection. Theoretically, 4-1BB [comes with] less CRS, so it should also result in [fewer] infections. Although this has not been looked at schematically, to directly correlate the signaling domain and the risk of infections, this can be extrapolated.

Then, what happens after CAR T-cell therapy? When patients develop CRS and ICANS, how are they treated? What is the cumulative dose and duration of corticosteroids that they receive? That impacts long-term early and delayed infection risk. These are some of the real determinants of CAR T.

Moreover, it is important to mention target antigens. There are no head-to-head data with target antigens, but one can hypothesize, based on cell surface expression patterns across B-cell lineage between BCMA and CD19, for example, that although CD19 will lead to more bacterial infection, BCMA is likely to result in more viral infection, as well as overall infection. We can hypothesize based on primarily preclinical data and a certain degree of speculation that BCMA CARs will lead to more infection; the cumulative incidence of overall viral and fungal infections will be higher with BCMA-directed therapies, whether they are bispecific T-cell engagers or a CAR T, as compared with CD19.

Shifting to the use of CAR T-cell therapies during the COVID-19 pandemic, what are some of the existing concerns with leveraging this modality in this context? What is your advice for your colleagues who are considering utilizing these therapies in practice for the patients who need them most?

It is important to remember that patients who need CAR T must receive it. Most of these patients have relapsed/refractory disease after having received another cell therapy or having undergone allogeneic or autologous transplantation. There are certain principles that every [treatment] center should follow, and some higher-level discussions that should be conducted based on hypothetical presumptions.

Some studies are seeking to evaluate survival outcomes in CAR T-cell recipients. For example, a recent study published in The Lancet Hematology showed that in a pooled cohort of 318 patients, which included autologous and allogeneic transplant recipients, 30% of CAR T recipients died at 30 days. That is an excruciatingly high mortality. Despite receiving the sophisticated, durable CAR, a very engineered advanced immune-engaging therapy, if patients contract COVID-19, their chances of survival are not good.

As such, it is important to stick to the basics. Telemedicine should remain at the core [of care]. Also, every effort should be made to vaccinate the patient [against the virus]. All their caregivers, all their healthcare providers, and all people [in their close circles] should be vaccinated; this is imperative. Their exposure to the community and to the hospital setting should be minimized and follow-up should be [done via] telemedicine.

We know that corticosteroid usage redistributes a patient’s T-cell repertoire, but it also blunts their response to vaccines. Corticosteroids can be used for the treatment or prophylaxis of CRS or ICANS or they can be used for the treatment of COVID-19 in CAR T recipients. However, we must be judicious; we must [think this] through prior to making that decision.

What has been observed thus far regarding vaccine response in this population?

We do not have enough data on this. However, [a small number of] studies, primarily transplant studies, have included a small subgroup of [those who have received] CAR T-cell therapy. Of these efforts, the first study to check cellular response in addition to antibody [response] was done in Israel. The issue with these studies is that they are not using the same immunoassay to measure antibody response. None of the studies, except for 1, checked cellular response.

The pooled response rate of 41 patients across 3 studies that utilized the same method of detection for antibodies is about 28%. The bigger caveat is that there is interassay variability. We need to know that the spike binding and neutralizing antibody titers are not validated among any group of immunocompromised patients. Moreover, the level of humoral response that correlates with clinical protection is not known. The response rate in [patients who have undergone] allogeneic transplantation ranges from 20% to 30% at most. CAR T-cell recipients are responding to SARS-CoV-2 vaccines in an even more dismal fashion.

How do you approach the topic of vaccination for these patients who do need to receive CAR T-cell therapy in your practice? What is known about determinants of response?

First, even if [patients] have received the SARS-CoV-2 vaccine prior to CAR T-cell infusion, they should be revaccinated following infusion, as they lose their response after CAR T. Moreover, response rates are not as good if they received SARS-CoV-2 vaccination within 6 months of CAR T-cell infusion. Therefore, if they started the vaccination series 6 months following CAR T, their responses were depleted; this is probably because by 6 months or longer, they have better immune reconstitution.

There are CAR T-related determinants of response and vaccine-related determinants of response. Regarding vaccine-related determinants, the type of the vaccine may matter. Let me make a hypothesis here: CAR T-cell recipients are likely to respond better to the Moderna vaccine, primarily due to 2 reasons. The first is that the Moderna vaccine has a higher messenger RNA spike content than the Pfizer vaccine. The other is that the duration between the 2 doses matter in CAR T, so 28 days vs 21 days. Serial conversion rate is likely to be higher [with Moderna], and durability is likely to be higher. Of note, I have no affiliation with either of these pharmaceutical companies.

Type of vaccine and messenger RNA content between CAR T and the first vaccine dose, duration between the first and the second vaccine dose, and the duration between the last vaccine dose, whether it's a second, a third, or any supplemental dose or booster, and response assessment—all of that matters. If response is assessed on day 14, they may not have good responses. If responses are assessed farther out, they may have good responses.

Pertinent CAR T–related factors that may drive humoral responses to SARS-CoV-2 vaccine include median IgG levels at the time of vaccination and CAR T target antigen. [CAR T-cell recipients] may not respond as well to BCMA CARs vs CD19 [CARs], although this is just a hypothesis. T- and B-cell lymphopenia at the time of vaccination, status of the underlying disease before vaccination, allogeneic transplantation prior to receiving CAR T, ongoing treatment, [and] immunosuppression status at the time of vaccination, are all factors that will drive and eventually dictate the response to the SARS-CoV-2 vaccine in CAR T-cell recipients.

You mentioned several challenges with the research that is currently available and expressed the need for more data. Where should efforts be focused going forward? What is your take-home message for your colleagues?

Despite the number of additional doses, if a CAR T-cell recipient does not mount humoral responses to 2 doses, the chances that the patient will respond to the third or fourth dose [are low]. I do not necessarily like to refer to the third dose a ‘booster dose’ because it may or may not boost immune response. A third dose may provide CAR T-cell recipients with a false sense of security, one that may start to change their behavior; this should not happen. Patients should continue to be counseled, continue isolation and mitigation strategies, and [practice the infection prevention strategies] that have been in place over the past year and a half.

Blood and Marrow Transplant Clinical Trials Network in collaboration with the Center for International Blood and Marrow Transplant Research is doing a nicely designed, prospective study. Other centers are also conducting prospective studies. We must use immunoassays that have been validated and have been shown to correlate with protective immunity. Otherwise, they are just numbers. There must be homogeneity in reporting.

[Investigators] in the cellular therapy community need to come together and standardize the protocols of all these prospective studies: response assessment methods, timelines, durations, and intervals of assessment. It is known that cellular responses to SARS-CoV-2 [vaccines] are equally important as antibody responses. In recent studies, the entire focus has been on checking antibodies. Moving forward, we need to focus should be on all-inclusive, concerted efforts on preventing vulnerable CAR T-cell patients from developing COVID 19.

Reference

1. Meir J, Abid MA, Abid MB. State of the CAR-T: risk of infections with CAR-T therapy and determinants of SARS-CoV-2 vaccine responses. Transplant Cell Ther. Published online September 26, 2021. Accessed October 26, 2021. doi:10.1016/j.jtct.2021.09.016