Part 2: CAR-T cell therapy and its complications

Could some complications of CAR-T cell therapy be secondary to HHV-6 infection?

Chimeric antigen receptor (CAR) T-cell therapy creates, ex vivo, T cells engineered to target cells bearing specific tumor cell antigens. Infusion of the CAR-T cells into patients with malignancies leads to sometimes dramatic reductions in the number and size of tumors, and to improvements in a patient’s outcome. Along with tyrosine kinase inhibitors and checkpoint blockers, CAR-T cell therapy has changed the face of cancer treatment in the past 20 years.

CAR-T therapy typically is given to patients with hematologic malignancies, especially those with B cell malignancies, and is being tested in some solid tumors. When used in people with relapsed or refractory diffuse large B-cell lymphoma, for example, the 2-year progression-free survival can be as high as 40%; the prognosis for this patient population without CAR-T therapy is poor (2-year overall survival, 20%) (Spanjaart 2022)

The adverse effects of CAR-T cell therapy

However, CAR-T cell therapy also is accompanied by several serious adverse effects, including mental status changes, cytokine release syndrome, pneumonia (of both known and undetermined cause) and bone marrow depression (decreased numbers of red blood cells, various white blood cells and platelets).

In one large multi-center trial (ZUMA-1), clinically important “neurological events” occurred in 32% of patients (with several more neurological events in the following year) and cytokine release syndrome in 11% of patients in the first year following therapy. Bone marrow depression occurred in 8-30% of patients. The events were described as “manageable and largely reversible”, although the report contains no detailed description of any residual deficits there may have been.  And the events were described as “not related to treatment,” although no explanation was given as to how that conclusion was reached. (Locke 2019)

In contrast, in another smaller trial, cytokine release syndrome occurred in 77% and neurological problems in 40% of patients. The neurological problems were “managed with supportive care”, and no information was presented as to the long-term neurological outcome.  (Maude 2018)

The cause of these neurological, immunological, pulmonary and hematological complications is obscure—in specific cases, and in general. When neurological abnormalities are detected early in the course of treatment, a diagnosis of immune effector cell–associated neurotoxicity syndrome (ICANS) often is made.  But the cause of this condition also is unknown.

Could some complications result from an infectious agent?

People undergoing CAR-T cell therapies are particularly vulnerable to infection. Those with hematologic malignancies already are heavily pretreated and significantly immunosuppressed. In addition, lymphocyte-depleting chemotherapy is given before CAR-T infusion. Also, immunosuppressive treatment for cytokine release syndrome typically involves treatment with anti-interleukin (IL)-6 or IL-6 receptor monoclonal antibodies and with immunosuppressive high-dose corticosteroids. The neurological condition, ICANS, is also treated with high-dose corticosteroids.

As would be expected in the face of such immunosuppression, a number of infections are reported more frequently in CAR-T cell therapy. The largest study to date found that of 133 patients 43 developed infections including 17% bacterial, 8% viral and 3% fungal (Hill 2018). Reactivation of HHV-6 has not been systematically examined in many studies of CAR-T cell therapy.

HHV-6 in Hematopoietic Cell Transplantation

It makes sense that HHV-6 could contribute to complications of CAR-T cell therapy, since it can cause complications following hematopoietic cell transplantation (HCT), a different treatment for hematologic malignancies also involving considerable immunosuppression.

HHV-6 reactivation occurs in 30%–70% of patients undergoing HCT, typically 2–4 weeks following transplantation. Most patients with HHV-6 reactivation are asymptomatic; however, 1-3% may develop encephalitis (Rebechi 2021).

Among those that develop HHV-6 encephalitis following HCT, however, the consequences can be severe.  In one series of recipients treated with antiviral therapy, the overall survival was approximately 60% after 100 days, with severe irreversible neurologic sequelae in 57% of survivors (Ogata 2017).

Part 3. HHV-6 Encephalitis in CAR-T Cell therapy

Part 4. Might HHV-6 contribute to some cases of cytokine release syndrome, pneumonia, and cytopenias in CAR-T Cell therapy?

Read the full paper: Lareau 2023