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signaling domain. Indeed, second generation CARs have shown robust antitumor activity in patients in the
setting of hematological malignancies. In third generation CARs, the main difference compared to second-
generation CARs is the inclusion of two costimulatory signaling domains. The costimulatory additions aim
to amplify the anti-tumor effect of second generation CARs, however, it remains to be determined whether
the inclusion of additional co-stimulatory domains improves CAR function. The fourth-generation CARs
are referred as T-cell redirected for universal cytokine killing (TRUCK) - and a variety of cytokine genes
[13]
have been added to this structure . There have also been recent creative designs that involve infusion of
[27]
nanoparticles aimed to enhance T-cells anti-tumor response and synthetic Notch (synNotch) receptors to
[28]
increase tumor specificity . Inducible CAR systems are also being developed by many researchers centered
around the idea that the T cells would only turn “on” and become cytotoxic in the presence of certain other
[12]
drugs - for example, a tetracycline regulation system that only turns on with doxycycline introduction .
Dual targeting CARs have also been developed that can target different receptors and induce signaling that
will results in different outcomes - for example, one pathway elicits cytoxicity while another promotes the
[14]
proliferation of T cells .

CAR-T CELLS IN SYSTEMIC CANCER
The first clinical application of CD19 CAR-T therapy allowing for the products to be studied for their efficacy
in humans was initiated in 2005 (NCT00182650; PMID: 20304086). Multiple clinical trials since then have
shown impressive outcomes in patients with relapsed, refractory B-cell hematologic malignancies. This
includes pediatric lymphoblastic leukemia (ALL), aggressive B cell non-Hodgkin’s lymphoma, and chronic
lymphocytic leukemia (CLL) [15-21] . The response has not only been dramatic in terms of overall response
rate and complete remission rate progression-free survival, but it has also been very durable in the majority
of cases. Consequently, on August 30th, 2017, the first anti-CD19 CAR-T cell product, tisagenlecleucel,
was approved for the treatment of children and young adults with relapsed or refractory B-cell precursor
ALL and subsequently also for the treatment of aggressive B cell lymphoma [21,22] . This was followed by the
approval of axicabtagene ciloleucel, another autologous anti-CD19 CAR-T cell therapy for the treatment of
[23]
relapsed large B-cell lymphoma, in October of 2017 .
CAR-T CELLS IN BRAIN CANCER
CAR-T cell therapy has shown tremendous clinical success in the treatment of hematological malignancies
and also solid tumors extending to the central nervous system (CNS). Within the JCAR017 clinical trial,
Abramson reported a case study of a 68-year-old patient with a systemic refractory diffuse large-B-cell
lymphoma who had developed a new brain lesion in the right temporal lobe. The patient was given CD19-
[24]
targeted CAR-T cells and exhibited complete remission for 12 months in the absence of any neurotoxicity .
Interestingly, CAR-T cells were identified in the cerebrospinal fluid (CSF) after systemic administration,
suggesting an alternative delivery route and their ability to cross the blood brain barrier, and trigger a
durable anti-tumor response [25,26] .

Several clinical trials across the nation are evaluating the efficacy of CAR-T cell therapy for patients with pri-
mary neuro-oncological malignancies. Multiple institutions are looking into several tumor targets as well as
alternative delivery routes for optimal anti-tumor response. Brown et al. described three patients with re-
[27]
current glioblastoma treated with first-generation interleukin-13 receptor alpha 2 (IL13Rα2) redirected CAR-
T cells. Using an Ommaya reservoir, patients were given up to 12 intracavity infusions with two patients
showing transient antitumor response. CNS inflammation was observed in all three patients and the degree
of inflammation appeared to correlate with IL13Rα2 antigen expression. This indicated a persistent anti-
tumor response through the activation of CAR-T cells once they recognized and were bound to the TAA .
[27]
[28]
Additionally, Brown et al. reported the use of second-generation CAR-T cells targeting IL13Rα2 in a pa-
tient with recurrent multifocal leptomeningeal glioblastoma (GBM). The patient showed no disease progres-
sion at the tumor site receiving CAR-T cell infusions via an Ommaya catheter; however this intratumoral