Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

 

Authors:

• Sattva S. Neelapu, M.D., Frederick L. Locke, M.D., Nancy L. Bartlett, M.D., Lazaros J. Lekakis, M.D., David B. Miklos, M.D., Ph.D., Caron A. Jacobson, M.D., M.M.Sc., Ira Braunschweig, M.D., Olalekan O. Oluwole, M.B., B.S., M.P.H., Tanya Siddiqi, M.D., Yi Lin, M.D., Ph.D., John M. Timmerman, M.D., Patrick J. Stiff, M.D.,

23/4/18

Presented by Tom Hartington

Background:

Axicatbagene Ciloleucel(axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has previously been through a phase 1 clinical trial. CAR T-cells are a form of adoptive immunotherapy that involves redirecting patients T-cells towards antigens expressed by cancer cells. CD19 is widely expressed throughout B cell development until the plasma cell stage. CARs are made up of antibody binding domains connected to a hinge region and intracellular T cell signalling molecules. Binding of antigen to the CAR results in effector function of the T cells including cytokine production, cytolytic activity and proliferation.

Clinical efficacy of axi-cel was demonstrated in patients with refractory diffuse large B-cell lymphoma (DLBCL( following failure of standard of care therapies. DLBCL is the 7^th most common cancer in the US and is the most common type of non-Hodgkin lymphoma. In refractory cases according to the recent SCHOLAR-1 trial patients have an objective response rate of 26% (complete response rate 7%) and median overall survival of 6.3 months. This demonstrates a severe clinical need for improved therapies. Following successful phase I trials axi-cel was taken into phase 2 testing.

Trial Overview:

A phase 2 trial  of axi-cel enrolled 111 patients across 21 centres in the US and 1 in Israel. Patients were enrolled who had diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) who had refractory disease following recommended prior therapies. Refractory disease was defined as progressive or stable disease as the best response to most recent therapy or disease progression or relapse within 12 months of autologous stem cell transplant.

Patients underwent leukapheresis, cells were transported to a central manufacturing facility for production of autologous anti-CD19 CAR T cells. Patient cells were transported to a single central manufacturing facility for manufacturing of ax-cel. This process included enrichment of T cells, activation, transduction with the CAR constructs, expansion, harvest, quality control and cryopreservation followed by the transportation of the cells to the clinical site. The median time of cell collection to delivery to the treatment facility was 17 days.

Patients received conditioning chemotherapy of fludarabine (30mg/m²) and cyclophosphamide (500mg/m²) on days -5, -4, -3. 2×10⁶ axi-cel CAR T-cells were administered per kg body weight on day 0. The primary endpoint of the trial was ORR (Objective response rate), calculated as complete response rate (CRR) combined with partial response rate (PRR) as defined by the International Working group response criteria for malignant lymphoma. Secondary end points included duration of response, progression free survival, overall survival, incidence of adverse events & blood levels of CAR T-cells and serum cytokines. Response rates were analysed to a prespecified historical response value of 20% for refractory DLBCL.

Axi-cel was successfully manufactured for 110 out of 11 patients and was administered to 101 patients. Patients who received axi-cel were included in a ‘modified intention-to-treat analysis. 77 patients had DLBCL, 24 PMBCL or TFL. The median age of patients was 58, the majority of patients had stage 3 or 4 disease, 77% of patients had disease resistant to second line or later therapies, 26% had primary refractory disease.

In primary analysis at 6 months, the ORR was 82% (95% CI 0.73-0.89) compared to the historical control response rate of 20%. Response rates were consistent across key co-variates including age, disease stage, prognostic index score at diagnosis, presence or absence of bulky disease, cell of origin type, CD19 histologic score, CD19 status, ratio of CD4/CD8 T-cells and use of glucocorticoids and tocilizumab . At the median follow up 15.4 months responses were ongoing in 43%.

Adverse effects of grade 3 or higher were reported in all patients who received axi-cel (84% neutropenia, 85% pyrexia, 66% anaemia, 38 % thrombocytopenia). Cytokine release syndrome (CRS) occurred in 95% of patients with 82% of them experiencing grade 1-2 CRS. CRS resolve in all but one patient who had grade 5 haemophagocytic lymphohistiocytosis. Neurological events occurred in 64% of patients including encephalopathy, confusional state, aphasia and somnolence. These did not resolve in 4 cases.

This trial gave evidence to suggest clinical benefit to patients with refractory disease. It confirmed the feasibility and reliability of providing personalised cell therapiey using a centralised manufacturing facility and co-ordination of leukapheresis procedures and shipping from multiple centres across the US. A limitation of the study was the lack of preplanned detailed analysis of molecular and cytogenetic characteristic of patient disease.

Group discussion points:

• Patient responses were seen in patients with reported no CD19 expression on tumour cells. The paper suggests that this may be an issue with the sensitivity of detection of CD19 levels. Other possible explanations could include the global effects of axi-cel T cells which could be activated by targeting CD19 expressed by healthy B cells resulting in immune stimulation that could activate endogenous anti-tumour T cell responses and antigen spread i.e. a response to tumour expressed antigens separate to CD19.
• The validity of a ‘modified intention-to-treat analysis’ was questioned as 10 patients who did not receive the drug either due to failure of manufacturing or disease progression were not included. This is despite the outcomes of these patients before administration being a key possibility for patients being managed with axi-cel due to the relatively long time for product manufacture in the context of an aggressive disease.
• The eligibility of patients was questioned. It was suggested that the use of patients who are relatively healthy in the disease context is necessary due to the high incidence of immune related adverse side effects from this type of immunotherapy. However, this restricts the scope of efficacy that can be demonstrated and gives no evidence as to the effectiveness or the potential use for more unwell patients with serious disease.
• The use of a ‘historical response rate’ was criticised as not being a particularly accurate or fair control. The reason for this in early phase 2 trials is sometimes that the focus is more on exploring side effect profiles of treatments as opposed to demonstrating efficacy.
• The cost of axi-cel is purported to be $373,000 not including other costs related to administration of CAR-T cell therapy. The cost effectiveness of this therapy was discussed with emphasis on the necessity of scaling of production costs and the need for evidence of long term clinical benefit to justify use of CAR-T cell therapies.

Key learning points

• Phase 2 clinical trials tend to have 100 or more patients enrolled. The purpose tends to be to assess side effects and to assess efficacy.
• The use of ‘modified-intention-to-treat analyses’ (mITT) is distinct from conventional ITT analyses. There is a potential source of bias in analysis by unjustified exclusion of patients from a mITT analysis.
• Adoptive cellular therapies are very expensive with prices of $300-500,000 for the cost of the product without taking into consideration the price of administration or management of side effects such as cytokine release syndrome which can require  ITU care.
• Immunotherapies in general cause a whole new range of side effects which have led to the creation of an immune related adverse side effects staging which is being used in clinical trials. Development of immunotherapies will create the need for training of clinicians to treat these often severe side effects such as cytokine release syndrome and autoimmunity.
• Targeted adoptive cellular therapies are showing some efficacy in targeting common cancer antigens in blood cancers however there are a limited number of targetable mutations which are common between different patients.
• CAR-T cells are yet to show a significant response in solid tumours, one possible limiting factor of this is targetable shared antigens. The success of therapies such as immune checkpoint inhibitors that activate an endogenous anti-tumour T cell response is correlated with tumour neo-antigen load in non-small cell lung cancer. Tumour neo-antigens tend to be private to the patient and therefore mass production of cellular therapies targeting them is unrealistic in the near future without significant technological advancements and reduction in production costs.

References:

• Neelapu, S., Locke, F., Bartlett, N., Lekakis, L., Miklos, D., Jacobson, C., Braunschweig, I., Oluwole, O., Siddiqi, T., Lin, Y., Timmerman, J., Stiff, P., Friedberg, J., Flinn, I., Goy, A., Hill, B., Smith, M., Deol, A., Farooq, U., McSweeney, P., Munoz, J., Avivi, I., Castro, J., Westin, J., Chavez, J., Ghobadi, A., Komanduri, K., Levy, R., Jacobsen, E., Witzig, T., Reagan, P., Bot, A., Rossi, J., Navale, L., Jiang, Y., Aycock, J., Elias, M., Chang, D., Wiezorek, J. and Go, W. (2017). Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New England Journal of Medicine, 377(26), pp.2531-2544.
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