CAR T-Cell Therapies – The Holy Grail of Therapeutic Innovation in Hemato-Oncology and its Challenges from a CRO Perspective
Giuseppe Lentini
Giuseppe Lentini
Senior Medical Director, Hematology/Oncology – Medical Affairs

Since the approval of the first IND for CD19 CAR T-cell therapy, which was approved and filed in 2007, tremendous advancements have been made in hemato-oncology indications, showing dramatic outcomes in patients with relapsed, refractory B-cell cancers including Hodgkin´s lymphoma, chronic lymphocytic leukaemia (CLL), adult and also paediatric acute lymphoblastic leukaemia (ALL) in early studies. These were also confirmed in larger series and transferred into other B-cell malignancies like multiple myeloma.

Marketing approvals for the first two commercially available CAR T-cell therapies Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel) accelerated clinical research activities in this unique field of gene therapy investigating on other target receptors and different indications within hemato-oncology, but also in immunology, inflammatory and regenerative medicine applications.

More than 1,000 patients have received CD19-targeted CAR T-cells in the United States so far.

From a CRO perspective, supporting R & D in this scientifically elegant and remarkably efficacious treatment, therapeutic expertise in managing the very specific toxicity-profile as also manufacturing and operational considerations based on extensive experience in immune-(cell) therapies, including more than a dozen of cell and gene therapies are of incredible help to make a study project successful in this incredibly exciting research area.


One feature which is specific of CAR T-treatment is that from a manufacturing and operational perspective, there is no possibility to date to provide a study site with a stock of pills or vials which can be assigned to a potential study subject. Each dose of a CAR T-treatment is entirely unique and specific to the patient receiving it. The treatment is custom-manufactured per patient, starting by harvesting some of the patient’s own cells, shipping these to a manufacturing facility, and over an approximate three-week manufacturing process, they are sorted, genetically modified and grown to a predefined volume or dose. The genetically modified living cells are infused back into the patient, and since T-cells are killer immune cells, and all B-cells (including those in B-cell leukaemia) express the CD19 protein, the treatment trains the patient’s own cells to kill the leukaemia.


The clinical risks and benefits of the two so far approved CAR T-treatments have been debated, discussing data from respective trials in children with relapsed or refractory B-cell acute lymphoblastic leukaemia – the sickest population of childhood leukaemia and patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. There are treatments available, but these diseases are mostly incurable and many patients relapse. Yet response rates for both treatments were high and for a long time. The data from these trials are statistically and clinically amazing. But, if this isn’t enough, the efficacy was summarized in FDA’s own briefing documents by stating, “The overall effectiveness of this product is not the primary issue for consideration by this Committee.”

The issues for debate were 1) how to safely manufacture a living product, and 2) how to manage the significant toxicity.


The spectrum of toxic effects associated with CAR T-cells differs from that of classic chemotherapy but also with checkpoint antibodies targeting programmed cell death 1 and cytotoxic T-lymphocyte antigen 4, in which the primary toxic effects are colitis, rashes and polyendocrinopathies. Many of the toxic effects that are reported with CAR T-cells are so called “on-target” effects. Their spectrum depends on the specificity of antibody single-chain variable fragments and T-cell activation. These toxic effects are thus reversible when the target cell is eliminated, or the engraftment of the CAR T-cells is terminated.

B-cell aplasia is a predicted on-target, off tumour adverse effect of CARs that target B-cell differentiation antigens such as CD19, CD20 and CD22. Clinical experience indicates that the

B-cell aplasia induced by CD19 CARs is more complete than that observed after antibody therapy with rituximab. Guidelines for the clinical treatment of patients with CAR-induced B-cell aplasia are evolving and may differ for children and adults, since children may have an incomplete long-lived plasma-cell compartment and weaker humoral immunity.

In some patients, CAR T-cells induce a clinical syndrome of fevers, hypotension, hypoxia and neurologic changes associated with marked elevations of serum cytokine levels. This spectrum of clinical and laboratory findings has been termed the cytokine release syndrome. The occurrence of the cytokine release syndrome is associated with both CD19 and B-cell maturation antigen (BCMA, also known as CD269) CARs, and in the case of CD19 CARs, the severity of the cytokine release syndrome is associated with tumour burden as measured by blasts in bone marrow at the time of treatment. The cytokine release syndrome manifests with a non-infectious flulike syndrome and can progress to life-threatening capillary leakage with hypoxia and hypotension.

Neurotoxicity appears to be a class effect with CD19-directed therapies because the same spectrum of toxic effects has been reported with blinatumomab, a bispecific anti-CD19 and anti-CD3 monoclonal antibody. The cause of the neurotoxicity remains unknown; it is usually fully reversible and not related to spread of cancer to the central nervous system (CNS). Cerebral edema has been reported in a subset of respective trials but has not been observed constantly in all trials; until the pathophysiology of the neurologic syndromes is explained, management remains empirical.

Manufacturing and Operational Considerations

The chain of custody starting from the patient’s first presentation to a hospital is to be considered for the therapy before manufacturing can begin. Lympho-depletion through high doses of chemotherapy, the manufacturing process and specific shipping conditions, are other considerations that are hugely paramount. Collectively, we have been involved in clinical trial operations for more than a dozen cell and gene therapies, and the significance of these operational considerations cannot be understated. We’ve witnessed first-hand the work that goes into managing this supply chain, and we’ve developed many best practices along the way to apply to future trials. One of which is to choose the right site which has proven competence in the clinical management of CAR T-treatment via a dedicated approval process and has been certified to prescribe the approved CAR T-treatments upfront. Certainly, these steps are a testament to the complexity of the manufacturing, operations, and treatment.

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