24 HOW TO TREAT : CELLULAR THERAPIES IN HAEMATOLOGY
24 HOW TO TREAT : CELLULAR THERAPIES IN HAEMATOLOGY
10 MAY 2024 ausdoc . com . au
PAGE 21 complications include iron overload , endocrinopathies and metabolic bone disease . Mental health disorders such as depression , anxiety and PTSD are common , and occur in up to 10-15 % of cases . 19
Regular review in a long-term follow-up clinic is required to prevent and manage long-term complications . Age-appropriate cancer screening includes regular skin checks , cervical screening tests , mammograms , prostate checks , colorectal cancer surveillance and examination for lymphadenopathy . Other management includes cardiovascular screening and risk factor management , bone densitometry , thyroid and gonadal function assessment . Ongoing psychological support is provided where appropriate .
DONOR T-LYMPHOCYTE INFUSIONS T-cells from the donor are sometimes infused following transplant to provide an additional GVD effect . Several specialised T-cell products are available , including regulatory T-cells , T-cells with an ‘ off ’ switch ( suicide gene therapy , that is , cells that can be turned off if they cause adverse effects ), and CMV- or Epstein – Barr virus-specific T-cells .
CAR T-CELL THERAPY
A CAR T-cell is a T-lymphocyte that has been genetically modified to gain specificity toward a specific antigen that is highly expressed on certain malignancies . CAR T-cells
T-CELL SOURCES CAR T-cells may be autologous or allogeneic . Autologous CAR T-cells are produced from the patient ’ s own T-cells that are then sent to a specialised processing facility ; a process which takes approximately four weeks .
Allogeneic CAR T-cell products are ‘ off the shelf ’ and contain modified T-cell receptors and / or HLAs to reduce the risk of GVHD . There are no currently approved allogeneic CAR T-cell products in Australia , although clinical trials are in progress .
Process
REFERRAL AND SUITABILITY ASSESSMENT A treating haematologist will refer patients in whom conventional treatment has failed to one of the CAR T-cell centres . A thorough assessment of the patient ’ s disease status and comorbidities is performed to determine their suitability for this procedure . While age is not a specific consideration when assessing suitability , frailty and performance status are useful indicators .
T-CELL COLLECTION AND CAR T-CELL PRODUCTION Using apheresis , mononuclear cells are collected from the patient and sent for processing . T-cells are isolated , enriched , activated and stimulated . Genetic material for the CAR is integrated into the T-cells using retroviruses , lentiviruses or genome
Figure 3 . Graft versus host disease .
Riddell SR et al . PLOS Med 2007 / CC-BY / bit . ly / 3Q2KpjN
CAR natural killer cells have the potential to allow improved efficacy with reduced adverse effects .
stimulate an immune response toward cells expressing the specific antigen , with the goal of providing an anti-tumour effect .
In 2018 the TGA approved the first CAR T-cell , tisagenlecleucel ( an anti-CD19 CAR T-cell ), for patients with relapsed B-cell precursor acute lymphoblastic leukaemia and relapsed / refractory diffuse large B-cell lymphoma ( see figures 5 and 6 ).
Several trials are currently underway investigating the role of CAR T-cell therapy in other conditions , including multiple myeloma , acute myeloid leukaemia , solid organ malignancies , viral infections , and as a vehicle for gene therapy .
Biology
MECHANISM OF ACTION A CAR is a synthetic receptor on the cell membrane of immune effector cells such as T-cells or natural killer ( NK ) cells that contains an immunoglobulin ( antibody ) fragment that is specific to a target antigen . The ‘ ideal target ’ antigen is expressed on the surface of all tumour cells , and not expressed on normal cells . However , true tumour antigens are relatively uncommon and most current CAR T-cell preparations target normal antigens that are also highly expressed on the malignant cell . CAR NK cells , currently under development , have the potential to allow improved efficacy with reduced adverse effects . 20 editing ( see figure 7 ). The T-cells are then expanded , harvested and frozen . Rigorous quality control is performed to optimise the number and quality of viable CAR T-cells .
CONDITIONING Before CAR T-cell conditioning , lymphodepleting chemotherapy is used to reduce the number of T-cells , B-cells and NK cells in the recipient , resulting in reduced anti-CAR T-cell immune response .
CAR T-CELL INFUSION Following conditioning treatment , CAR T-cells are infused , and patients are closely monitored for immune-related complications . Patients are generally treated as inpatients ; however , as technology improves it is anticipated that outpatient therapy may be feasible in certain situations .
Current international CAR T-cell trial results
Table 1 list the responses to treatment and survival data for CAR T-cell therapies .
Complications
IMMUNE COMPLICATIONS Several immune-related complications may occur following CAR T-cell therapy . 28
Cytokine release syndrome ( CRS ) is an inflammatory condition resulting from the release of cytokines by immune cells ; this occurs in 22-42 % of cases . 21 , 29 The
Table 1 . Response to treatment and survival data for CAR T-cell therapies Product Response to treatment Survival Relapsed / refractory diffuse large B-cell lymphoma
Tisagenlecleucel a ( Kymriah , anti-CD19 ) 21 , 22 ORR 52-62 % CR 40 %
Axicabtagene a ( Yescarta , anti-CD19 ) 23 , 24 ORR 82 % CR 58-62 %
Acute lymphoblastic leukaemia
RFS 65 % and OS 49 % at 12 months
PFS 44-45 % at 12 months and OS 52-64 % at 18 months
Tisagenlecleucel a ( Kymriah , anti-CD19 ) 22 , 25 CR 86 % EFS 50-52 % and OS 76 % at 12 months Relapsed / refractory follicular lymphoma
Axicabtagene a ( Yescarta , anti-CD19 ) 26 ORR 94 % CR 80 %
Multiple myeloma
Idecabtagene vicleucel ( Abecma , anti-B-cell maturation antigen ) 27 ORR 73 %
CR 33 %
PFS 74 % and OS 93 % at 12 months
Median PFS 8.8 months and OS 78 % at 12 months a
: currently TGA approved . ORR : overall response rate ; CR : complete response ; RFS : relapse-free survival ; PFS : progression-free survival ; EFS : event-free survival ; OS : overall survival .
Figure 4 . Graft versus host disease .