Our new paper on second infusions of CD19 CAR T-cells is finally out *in print* in @BloodJournal !
https://doi.org/10.1182/blood.2020006770
Time for a little Tweetorial 😄
Please retweet for your CAR T-cell friends/aficionados 😉
[THREAD 🧵] 1/24
@fredhutch @RyanCassaday
A lot of buzz around CD19 CAR T cell therapy, understandably, but clearly outcomes are perfectible.
In our experience using defined-composition CD19 CAR T cells, only 25-30% of large B cell lymphoma (LBCL) and B-ALL pts remain disease-free long-term. 2/24
A lot of buzz around CD19 CAR T cell therapy, understandably, but clearly outcomes are perfectible. In our experience using defined-composition CD19 CAR T cells, only 25-30% of large B cell lymphoma (LBCL) and B-ALL pts remain disease-free long-term. 2/24
A lot of buzz around CD19 CAR T cell therapy, understandably, but clearly outcomes are perfectible. In our experience using defined-composition CD19 CAR T cells, only 25-30% of large B cell lymphoma (LBCL) and B-ALL pts remain disease-free long-term. 2/24
One possible approach to improve outcomes would be to "redose" patients with a second infusion of CAR T-cells (CART2).
To date, very limited data and many questions remain:
How feasible to manufacture a second product?
Is it safe?
Does it work?🤔 3/24
In search for these answers, we took a retrospective look at 44 patients treated on a phase I/II clinical trial carried out at our institution @fredhutch
Key design characteristics/inclusion/exclusion criteria 👇 4/24
In search for these answers, we took a retrospective look at 44 patients treated on a phase I/II clinical trial carried out at our institution @fredhutch Key design characteristics/inclusion/exclusion criteria 4/24
In search for these answers, we took a retrospective look at 44 patients treated on a phase I/II clinical trial carried out at our institution @fredhutch Key design characteristics/inclusion/exclusion criteria 4/24
Patients received a repeat CAR T-cell infusion under three main scenarios:
1-Relapse or progression after initial response to first infusion (CART1)
2-Bad PR after CART1 (in most bulky residual disease)
3-No response after CART1 (primary refractory) 5/24
Without getting too much into the weeds, some key patient/disease characteristics:
- High % of EM disease in ALL (50%)
- Prior allo in 71% of ALL patients
- High % of bulky disease in CLL/NHL (67/48%)
To state the obvious: ultra high-risk population. 6/24
Without getting too much into the weeds, some key patient/disease characteristics:- High % of EM disease in ALL (50%)- Prior allo in 71% of ALL patients- High % of bulky disease in CLL/NHL (67/48%)To state the obvious: ultra high-risk population. 6/24
Without getting too much into the weeds, some key patient/disease characteristics:- High % of EM disease in ALL (50%)- Prior allo in 71% of ALL patients- High % of bulky disease in CLL/NHL (67/48%)To state the obvious: ultra high-risk population. 6/24
A few more things important to highlight:
- most ALL patients received a lower CAR T-cell doses compared to CLL/NHL to prevent severe toxicities
- in 82%, we increased the CART2 dose related to CART1 dose
*bonus* CAR-T jargon: 1 "log10" higher, ie, 2 x 10^5-> 10^6 -> 10^7) 7/24
How easy was it to make a new product?
Using our in-house manufacturing, we successfully manufactured a second CAR T-cell product using cryopreserved material in 95% of patients; in those, no need for a repeat leukapheresis!
8/24
How about toxicity?
Despite the CART2 dose increase in most patients, CRS and ICANS were mild in most patients, with grade 3-4 CRS and ICANS in 9% and 11%, respectively. 9/24
Did it work?
The efficacy was lower than what is seen after first infusions (ORR, 39%), but we did observe CRs in a subset of patients (20%), with higher response rates in CLL and NHL patients compared to ALL.
Some significant responses in some patients with bulky disease! 10/24
Did it work?The efficacy was lower than what is seen after first infusions (ORR, 39%), but we did observe CRs in a subset of patients (20%), with higher response rates in CLL and NHL patients compared to ALL.Some significant responses in some patients with bulky disease! 10/24
Did it work?The efficacy was lower than what is seen after first infusions (ORR, 39%), but we did observe CRs in a subset of patients (20%), with higher response rates in CLL and NHL patients compared to ALL.Some significant responses in some patients with bulky disease! 10/24
Using multivariable regression, we identified two actionable pretreatment factors associated with better outcomes after second infusions:
- CyFlu lymphodepletion prior to CART1
- CART2 dose > CART1 dose 11/24
In CLL/NHL patients who received CyFlu pre-CART1 and a higher CART2 dose the ORR was 71% with a median PFS of approximately 6 months. Outcomes were poor in the other groups 12/24
In the next set of analyses, we tried to connect these clinical factors (lymphodepletion and dose) to the in vivo CAR T-cell kinetics, which is known to be strongly associated with outcomes. 13/24
Good ol' multivariable linear regression showed that CyFlu lymphodepletion was associated with higher peak expansion of CAR T cells in vivo, even when adjusting for disease type, CD19 burden, dose.
Intriguingly the effect of dose on peak expansion was undetermined (p=0.59)🤔14/24
BUT when we looked at the data *longitudinally* (using my beloved LOESS smoother), increase in the CAR T-cell dose was associated with prolonged in vivo persistence! In other words, without the dose increase – DESPITE CyFlu pre-CART1 – loss of persistence was still swift. 15/24
As shown above, minute in vivo CAR T-cell expansion was measured in patients who did not receive CyFlu pre-CART1.
What's so *magical* about CyFlu?
One possible explanation: immunogenicity. 16/24
Supporting this hypothesis, we detected CD8+ anti-CAR immune responses after CART2 primarily in patients not exposed to CyFlu prior to CART1 (88% of patients tested).
In most patients, these CD8+ responses were mapped to aminoacid sequences in the murine scFv of the CAR. 17/24
Supporting this hypothesis, we detected CD8+ anti-CAR immune responses after CART2 primarily in patients not exposed to CyFlu prior to CART1 (88% of patients tested). In most patients, these CD8+ responses were mapped to aminoacid sequences in the murine scFv of the CAR. 17/24
Supporting this hypothesis, we detected CD8+ anti-CAR immune responses after CART2 primarily in patients not exposed to CyFlu prior to CART1 (88% of patients tested). In most patients, these CD8+ responses were mapped to aminoacid sequences in the murine scFv of the CAR. 17/24
The "Take home" messages...
Second infusions of CD19 CAR T cells:
- Feasible and safe
- Efficacious in a subset of CLL and NHL patients
- CyFlu prior to CART1 and higher CART2 dose associated with robust in vivo CAR T-cell kinetics and superior outcomes 18/24
Still, a lot of work ahead!
- Mechanisms of CAR T-cell failure remain poorly characterized
- Strategies to improve outcomes of retreatment with CAR T cells currently under investigations by many groups 19/24
Our clinical trial using defined composition CAR T-cells using a fully human scFv is currently open and enrolling @SeattleCCA @UW with a cohort dedicated to LBCL patients already exposed to a *murine* CAR T cell product (NCT03103971). 20/24
This would not have been possible without the tireless work of many, literally from bench to bedside!
I would like send special thanks to @E_D_Bezerra for his crucial help collecting and analyzing the data, and of course to my mentor the legendary Dr. Cameron Turtle ! 🙏🙏21/24
This would not have been possible without the tireless work of many, literally from bench to bedside! I would like send special thanks to @E_D_Bezerra for his crucial help collecting and analyzing the data, and of course to my mentor the legendary Dr. Cameron Turtle ! 21/24
This would not have been possible without the tireless work of many, literally from bench to bedside! I would like send special thanks to @E_D_Bezerra for his crucial help collecting and analyzing the data, and of course to my mentor the legendary Dr. Cameron Turtle ! 21/24
Also need to acknowledge the help from all co-authors! @xanhira @AlyssaSheih @ekimblepl @mshadman @andrewcowanmd @RachelSteinmet7
@TheHutchChapuis @HPKiem
Don't forget to follow them 😉 22/24
Last, I would like to thank Dr. Casucci and Dr. Ciceri @CiceriFabio from @SanRaffaeleMI for their thoughtful editorial accompanying our publication:
https://ashpublications.org/blood/article/137/3/284/474945/A-second-CD19-CAR-T-cell-infusion-yes-or-no 23/24
Congratulations! You made it to the end 😄
Was this thread helpful? 24/24
Importantly, I forgot to thank @JunoThera (now a @BMS_ImmunOnc_US company!) for funding this trial 🙏
You can follow @drjgauthier.
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