Q&A: CAR T cells may represent 'more thorough therapeutic approach' for glioblastoma

Chimeric antigen receptor T cells have emerged “as a promising therapeutic avenue” for the treatment of glioblastoma, though various factors still limit its efficacy, according to a review published in Neurology.

“Glioblastoma is the most common malignant primary brain tumor in adults and [is] characterized by a poor prognosis,” the researchers wrote. “Microsurgical tumor resection followed by concomitant radiochemotherapy and consolidation chemotherapy represents the 'standard of care.’ Despite such a multimodal therapy and intense research efforts in the last decade translating into considerable survival benefits, median survival has remained in the range of 15-18 months. Therefore, new therapeutic approaches in glioblastoma are urgently warranted.”

Immunotherapy characterizes “a major breakthrough” in the treatment of many solid tumors, as well as hematological cancers, according to the review published in Neurology. Specifically, genetically engineered chimeric antigen receptor (CAR) T lymphocytes have become “a promising class of immunotherapeutic agents” for relapsed or refractory hematological malignancies. However, it is less clear whether immunotherapy with CAR T cells could become a therapeutic avenue in solid tumors, including glioblastoma, the researchers noted.

Philipp Karschnia, MD, DSc, a neurosurgery resident in the department of neurology at the University Hospital Munich and Ludwig-Maximilians University in Germany, and colleagues reviewed the available data on CAR T-cell therapy for glioblastoma and challenges associated with its use, both in the context of glioblastoma and in general, as patients treated with CAR T-cell therapy “may present to the consult service with neurotoxic symptoms warranting specialized care.” According to Karschnia and colleagues, “a high level of suspicion is required” when treating patients who received CAR T-cell therapy, as certain drugs used to improve neurotoxic symptoms may inhibit the antitumor effects of CAR T-cell therapy.

Healio Neurology spoke with Karschnia and Louisa von Baumgarten, MD, DSc, of the departments of neurosurgery and neurology at Ludwig-Maximilians University School of Medicine and the German Cancer Consortium Partner Site, all of which are in Munich, to learn more about their findings.

Healio Neurology: What prompted this publication?

Karschnia and von Baumgarten: Adoptive immunotherapy with CAR T cells has become a substantial part of the therapeutic landscape for hematological malignancies. However, CAR T cells are not only a matter of interest for hematologists, but we also expect that general neurologists, and neuro-oncologists in particular, will be increasingly exposed to patients being treated with CAR T-cell therapy. On the one hand, such therapy is accompanied by unique toxicities, including neurotoxic symptoms. Neurologists need to not only understand how CAR T cells work but also how to ameliorate neurotoxic symptoms without diminishing antitumor effects facilitated by CAR T-cell therapy. On the other hand — and this is what we were primarily focusing on in this paper — there have been considerable efforts to translate CAR T-cell therapy into the treatment of patients with glioblastoma. Numerous studies are ongoing, and neurologists should be aware of this exciting and promising therapeutic avenue.

Healio Neurology: What is currently known about the effectiveness of CAR T-cells for glioblastoma?

Karschnia and von Baumgarten: There is a high level of evidence arising from murine in vivo models that CAR T cells may indeed exhibit clinically relevant antitumor effects against glioblastoma. Although some of these preclinical studies were limited due to immunocompromised mouse models, excellent fully syngeneic models have been designed and validated these promising data. First clinical experiences that have been published were less encouraging: Although some antitumor effects were seen on imaging or tissue analysis after treatment, patients still progressed and died within months. Importantly, these studies were primarily designed to assess the safety profile of CAR T cells in glioblastoma. There has also been a case report of a patient who had substantial disease regression after CAR T-cell therapy that lasted for 7.5 months. Collectively, we think that there might be some tumor response, but CAR T cells might not yet be as effective as they are in in hematological malignancies — but again, final data are not out yet.

Healio Neurology: What are the benefits and drawbacks to this therapeutic approach in glioblastoma?

Karschnia and von Baumgarten: Glioblastoma harbors a highly invasive nature and we now consider it a disease of the entire brain. Accordingly, local therapies, including surgery and radiotherapy, cannot offer a cure to affected patients. Assuming CAR T cells may travel across the blood-brain barrier even when intact, CAR T cells may provide an antitumor response throughout the entire brain. Compared with chemotherapy, CAR T cells may also tackle non-dividing tumor cells and may therefore be a more thorough therapeutic approach compared with local therapies or chemotherapy.

On a cautionary note, common and potentially life-threatening side effects of CAR T-cell therapy are seen in patients with hematological malignancies, including cytokine release syndrome of immune effector cell-associated neurotoxicity syndrome (ICANS). We do now know yet whether patients with central nervous system disease might be at higher risk for neurotoxic symptoms. Also, whether CAR T cells may indeed travel across the intact blood-brain barrier is still a matter of debate, and so is the optimal way of administration: intravenous vs. intrathecal vs. local.

Healio Neurology: What specific points did you make in your paper?

Karschnia and von Baumgarten: First, we outlined the basic structure of CAR T cells and the above-mentioned data on CAR T cells coming from preclinical as well as clinical studies. Next, we discussed why antitumor effects of CAR T-cells might be less pronounced in glioblastoma compared with hematological (and maybe also other solid) malignancies: Antigen expression on glioblastoma appears rather heterogeneous, and targetable mutations might be lost during later stages of the disease (and has been described as a potential escape mechanism in patients with glioblastoma, which progressed under CAR T-cell therapy).

Moreover, the glioblastoma microenvironment is highly immunosuppressive. This immunosuppression might be aggravated by steroids, which many glioblastoma patients depend on given the mass effect of the tumor.

We then highlighted how antitumor effects of CAR T cells might be optimized despite these hurdles. We argued that CAR T-cell design and the discovery of novel target antigens may help; it seems also crucial to find the optimal therapeutic sequence of CAR T-cell therapy in the context of other therapeutic approaches. For instance, surgery may form the basis of local CAR T-cell delivery into the resection cavity. Also, combination with other immunotherapeutic therapies such as checkpoint inhibitors may represent viable options to enhance CAR T-cell efficacy.

Healio Neurology: What are you hoping clinicians take away from your piece?

Karschnia and von Baumgarten: We are hoping to provide an overview on what CAR T cells are, how they work, why they might also work in glioblastoma patients and what factors may limit their efficacy in this peculiar patient population. Given that numerous studies on CAR T-cell therapy in adult and pediatric glioblastoma patients are ongoing, we believe that general neurologists may in the future provide care for this patient collective. Concomitantly, medical oncologists may participate in the care of patients with glioblastoma; we hope to highlight the inherent disease-specific biologic features of glioblastoma, which will be of relevance when administering CAR T-cell therapy.

Healio Neurology: What unmet research needs remain for CAR T-cell therapy in glioblastoma?

Karschnia and von Baumgarten: We are highly anticipating the data from ongoing prospective trials comparing CAR T-cell therapy to standard therapy. Once the final data on efficacy is out, we believe that there are many open questions to address regarding optimal target antigen, combinational strategies and CAR T-cell design.

Reference:

Karschnia P, et al. Neurology. 2021;doi:10.1212/WNL.0000000000012193.