In-house dual CAR T-cell therapy development

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy
has shown impressive results in patients with heavily pretreated multiple
myeloma (MM).
However, relapses still occur, which may be explained by reduced target antigen
expression on tumor cells and low persistence of CAR T-cells.
The Amsterdam UMC is currently developing CAR-T cell therapy for patients with
MM. Laboratory research with healthy donor T-cells demonstrated that a CAR
targeting BCMA, in combination with a CD38 chimeric costimulatory receptor
(CCR), results in high affinity, efficient CAR T-cells with good persistence.
A next step to validate these findings is using T-cells of MM patients. It is
reasonable to expect that MM patients will have reduced T-cell functionality
either due to the disease itself, but especially due to previous treatment with
drugs known to hamper T-cell function.

To investigate the production of sufficient numbers of effective CAR/CCR
T-cells with T-cells obtained from blood of MM patients.

Pre-clinical in vitro study.

Patient groups:
Group 1A: Triple refractory MM patients (n=5)

Group 2A: MM patients; treated with BsAbs either on treatment or within 3
months after discontinuation (n=5).

Group 1A and 2A are expected to be most challenging due to previous treatment.
If showing efficacy in small scale (6 well-plate) (when >=4 out of 5 experiments
meet the study endpoints), this will be extended to a patient scale (fully
GMP-compliant closed-system process with the Lonza Cocoon) in vitro experiment
(n=5 per group).

If CAR/CCR T-cell production fails (small or full scale, when <4 out of 5
experiments meet the study endpoints) with T-cells from patients described in
group in 1A and/or 2A, it will be investigated in group 1B, 1C and/or 2B, again
first small scale, if successful (again when >= 4 out of 5 experiments meet the
study endpoints) also full scale.
- Group 1B: MM patients having received first line treatment only (n=5)
- Group 1C: Non-treated newly diagnosed MM patients (n=5)
- Group 2B: MM patients >3 months after BsAbs treatment discontinuation (n=5)

Patients will undergo extra blood sampling during a routine visit.
For the small scale experiment the quantity will be 50 ml. This amount is not
harmful for the patient.


For the full scale experiment the quantity will be 200 ml. This amount may
cause dizziness or a lower blood pressure in some patients. Blood withdrawal
will be performed at the day care and will extend their visit to 60minutes.
Visits are combined with a standard of care visit.

There is no primary benefit for the patients participating.
Future patients may possible benefit from more accessible and possible
efficient CAR T-cell therapy.