Alpha/Beta T-Cell Depletion – Transforming Pediatric HCT

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Alpha/Beta T-Cell Depletion –Transforming Pediatric HCT

Christopher C. Dvorak, MDProfessor and Chief

Division of Pediatric Allergy, Immunology, and Bone Marrow TransplantationUniversity of California San Francisco

Faculty Disclosure• Consulting for Alexion, Inc., Omeros Corp., and Jazz

Pharmaceuticals• Alpha-Beta TCR T-cell Depletion is made by Miltenyi

Biotec and is investigational in the US (all procedures done under an IND/IDE)

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In compliance with ACCME policy,AABB requires the followingdisclosures to the session audience

Objectives• Describe how Alpha/Beta T-cell Depletion is

performed• Contrast the pros/cons of in vivo and ex vivo T-cell

depletion strategies in pediatric patients undergoing haploidentical HCT

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For Allogeneic HCT, There are 4 Donor Options• Matched Sibling Donor (MSD)

– Historically, the gold standard– Rejection rare, GVHD uncommon– For cancer, MSD has least GVL effect, and for genetic diseases, some carrier issues

• Adult Unrelated Donor (URD)– Success depends on mainly on degree of match

• Unrelated Umbilical Cord Blood (UCB)– Success depends on mainly degree of match and cell dose

• Mismatched Related Donor (MMRD; Haploidentical)– Readily available for most patients– Success depends on degree of T-cell depletion (TCD)– TCD can be done either in vivo or ex vivo

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Likelihood of Finding Unrelated Donor or UCB

Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.

0%10%20%30%40%50%60%70%80%90%

100%M

atch

like

lihoo

d

Ancestral group of searching patient for hematopoietic cell transplantation

8/8 HLA adult donor 7/8 HLA adult donor 6/6 HLA cord blood 5/6 HLA cord blood 4/6 HLA cord blood

MSD HCT has been flat for the last 20 years

MUD HCT has been flat for the last 8 years

Haplos are the cool new thing!

UCBT may be nearly extinct by 2025 (except for certain rare diseases)

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Haplo HCT Has Gotten a Lot Better!

1991-1999 2000-2007• Early haplosdone mainly with CD34 selection

• Recent haplos done mainly with CD3 depletion

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What is the Best Way to Prevent GVHD after HaploHCT Without Eliminating GVL?

CD4+ & CD8+ T Cells Mediate GVHD: These Have A/B TCRs

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Different Haplo OptionsIn Vivo TCD: PTCYEx Vivo TCD

A/B TCDCD34 Selection

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• PBSC Collection• Requires excellent stem

cell lab (and an IND)• Fast Count Recovery• No Pharmacologic

GVHD Prophylaxis needed

• No exposure of HSCs to alkylation

• BM Collection• Anyone can do it• Slower Count Recovery• Requires Tacro and

MMF• Exposes donor HSCs to

alkylation -> 2nd

malignancy?

A/B TCD vs. PTCY

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A/B TCD: Processing

• You also need to co-remove CD19+ cells• Expect some CD34+ cell loss: Median recovery = 78% (range 49-93%)• We aim to collect 2x the goal CD34 target of 10x10^6/kg• This is typically not an issue with smaller kids (<20 kg) and parental

donors, but can be a problem with AYAs and when haploidentical siblings are used -> multi-day collections

• The A/B T-cell Depletion can be quite profound (final dose in the graft is typically <1 x 10^5 cells/kg) -> Add-back may be desirable

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Optimizing Cell Dose: RejectionCD34 dose > or < 10 x 10^6/kg A/B T-cell dose > or < 8 x 10^4/kg

9% vs. 44% (p=0.006) 0% vs. 23% (p=0.044)

N=9

N=17

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N=43N=34

Unpublished Data from 52 First Haplo HCTs for Heme Malignancy at UCSF

Is A/B TCD Worth All The Effort?• A/B TCD• Single Center Italian

Prospective Data (N=80, 2011-2014)

• Multi-Center US Prospective Data (N=51, 2015-2020)*

• Single Center UCSF Retrospective Data (N=52, 2015-2021)

• PTCY• Single Center US

Prospective Data (N=29, 2008-2016)

• Multi-Center European Retrospective Data (N=180, 2011-2019)

13*Presented as a best Abstract at ASTCT 2021

Is A/B TCD Worth All The Effort?Non-Relapse Mortality: A/B TCD

Locatelli, et al. 2017 5% (5 years)

PTCTC ONC1401 10% (2 years)

UCSF 4% (2 years)

Non-Relapse Mortality: PTCY

Symons, et al. 2020 7% (1 year)

Ruggeri, et al. 2021 20% (2 years)

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Relapse: A/B TCD



UCSF 15% (2 years)

Relapse: PTCY

Symons, et al. 28% (3 years)

Ruggeri, et al. 42% (2 years)

Is A/B TCD Worth All The Effort?

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Relapse-Free Survival: A/B TCD



UCSF 81% (2 years)

Relapse-Free Survival: PTCY

Symons, et al. 2020 65% (3 years)


Overall Survival: A/B TCD



UCSF 91% (2 years)

Overall Survival: PTCY

Symons, et al. 2020 79% (3 years)


A/B TCD Has Made Haplo Equivalent to Other Donors (in Terms of Safety)

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Haplo (n=83)

MSD(n=38)

URD (n=59)

Unpublished Data from All First HCTs for Heme Malignancy at UCSF from 2016-2020

A/B TCD Haplos vs. Other Donors: NRM

Data courtesy of M. PulsipherItalian Data (Bertaina, Blood 2018)

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There Is No Such Thing as a “Good Donor”• The likelihood of finding a perfectly matched donor

depends on the patient’s ancestry as compared to the donors in the registry, not offering BMT to patients without a perfect match is perpetuating a medical disparity

• “We’ll go to transplant if there is a matched sib or a good unrelated donor”

• All patients who need a BMT for best control of their underlying disease should be offered a BMT, regardless of their donor options

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The Next Steps

• We have made haploidentical HCT as safe as other donors

• Could it actually be superior?• For patients with heme malignancies undergoing

HCT, the biggest problem is not TRM, but relapse• The HLA mismatches of haplo HCT induce a

powerful GVL effect

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MMURD

UCSF Data: Relapse by Donor

MSDURD

Haplo

Other factors statistically associated with Relapse:• MRD POS (p=0.005)• Conditioning Type (p=0.013)

P=0.016

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Haplo

MMURD

URD MSD

P<0.001

Other factors statistically associated with RFS:• MRD POS (p=0.006)• Conditioning Type

(p=0.009)• HCT-CI (p=0.031)

UCSF Data: RFS by Donor

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A/B TCD Haplos vs. Other Donors: LFS

Data courtesy of M. Pulsipher

Italian Data (Bertaina, Blood 2018)

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What Donor to Choose Based on MRD Status?

MSD URD MMURD Haplo

23Unpublished Data from All First HCTs for Heme Malignancy at UCSF from 2011-2020

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Conclusions• Haploidentical HCT allows HCT for all patients, regardless of ancestry• A/B TCD Depletion is labor intensive, but has many attractive

qualities compared to in vivo TCD with post-transplant cyclophosphamide

• For patients with heme malignancies, A/B TCD Haplo HCT is as good, if not better, than MSD or URD HCT

– Especially if the patient is minimal residual disease positive (due to the strong GVL effect of haplo)

• A/B TCD Haplo can be a platform for other graft engineering techniques

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Acknowledgments• Entire UCSF Pediatric HCT Team (MDs, NPs, RNs, SW, Pharmacy, etc.) • Mort Cowan – 1st Haplo on the West Coast in 1982• Mike Pulsipher (CHLA) – Said “Let’s do a A/B TCD HCT Trial in the US!”

– Hisham Abdel-Azim (CHLA) – Led data analysis of PTCTC ONC1401– Alice Bertaina (Stanford) – Led the Italian trials– NCI R01 CA181050 (Pulsipher)

• Apheresis Programs (Adult & Pediatric) – Collecting high numbers of CD34+ cells required is challenging!

• Importantly, PCTL Staff led by Sherman Bakabak and Jess Oh– A/B TCD is a LOT more work than just giving PTCY, but I think it’s worth it!

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Thank You!

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Pediatric Cellular Therapy: An Overview from Collections to Alpha/Beta DepletionsAlpha/Beta T-Cell Depletion –Transforming Pediatric HCT

17 October 2021 (1500-1600)

A Problem: OS Rates Have Mainly Stalled

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0 3 6 9 12 15 18 21 24

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MONTHS AFTER TRANSPLANT

2013–2016 (n=305)2009–2012 (n=216)2004–2008 (n=173)1987–2003 (n=140)

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2013–2016 (n=235)2009–2012 (n=257)2004–2008 (n=196)1987–2003 (n=206)

ALL AML

SOURCE: CIBMTR®, the research program of NMDP/Be The Match

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http://www.cibmtr.org/

Is A/B TCD Worth All The Effort?

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9.8 & 19.8%

CR1=39% of patientsCR2+=61% of patients

What Donor to Choose Based on HCT-CI?

MSD URD MMURD Haplo

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Generally in Good Shape In Poor Shape

Unpublished Data from All First Haplo HCTs for Heme Malignancy at UCSF from 2011-2020

Alpha/Beta T-Cell Depletion – Transforming Pediatric HCT

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