Transfer of vaccine-induced immunity from immunocompetent stem cell donor as antiviral immunotherapy to protect high-risk transplant recipients from cytomegalovirus reactivation

Active Project Grant Awarded Last action

Award ID
R01CA266783
Recipient
Awarding agency
Obligated
$5,793,108

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 69% complete
Place of performance
Irwindale, CA 91010, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Preemptive use of antivirals (pet) to control cytomegalovirus (CMV) viremia in hematopoietic cell transplant recipients (HCT-r) was a therapeutic advance balanced by elevated toxicity. Newer drugs such as letermovir (prevymis) have lower toxicity with increased efficacy. FDA approval of prevymis was for 100 consecutive days (d) of prophylaxis which reduced CMV reactivation by ~2FOLD in high and low risk HCT-r. The antiviral effect waned after 18 weeks without a survival benefit. We CO-developed with NCI, a modified vaccinia ankara (MVA) vaccine named triplex expressing CMV immunodominant antigens. We published a safety study in healthy volunteers showing strong immunogenicity of the vaccine (NCT1941056), which preceded a published successful placebo-controlled and randomized phase 2 trial (NCT2506933) of CMV-positive (p) HCT-r with either CMV-positive (CMV-p) or CMV-negative (CMV-n) HCT donors (HCT-d). The phase 2 trial met its primary endpoint of reduced CMV reactivation in the vaccine arm by 50% with accelerated reconstitution of protective CMV immunity. Triplex outcomes can be improved; one approach is to vaccinate the immunocompetent HCT-d as demonstrated by our impressive preliminary results from an ongoing pilot study (NCT3560752) which showed that all HCT-r (n=12) receiving stem cells from vaccinated matched related donors (MRD) were protected from requiring pet. We hypothesize that triplex injection of HCT-d will initiate protective immunity by transfer of expanded CMV-protective t cells as a component of the stem cell infusion to the HCT-r, preceding dosing with prevymis, thereby eliminating its need. In aim 1, we propose a phase 2 randomized placebo-control trial (in centers not prescribing prevymis for MRD-HCT) with eligibility of CMV-p HCT-r with MRD (intermediate risk) undergoing t-cell replete HCT for hematologic malignancy. CMV-p HCT-r will be randomized to receive stem cells from HCT-d receiving a single injection of triplex or placebo identical to the pilot trial. This trial will show that a single HCT-d vaccination is sufficient to replace 100D of prevymis to prevent pet usage in MRD-HCT-r. In the 180D trial period we will assess pet usage, measure CMV-specific CD8/CD4 t cells with the goal of associating frequency, memory phenotype, and gene expression with protection against reactivation leading to viremia or disease. To extend triplex benefit to haploidentical HCT-r treated with post-HCT cyclophosphamide (ptcy) who are at high risk for CMV reactivation, in aim 2 we propose a two-stage (phase 1B/2) trial to choose an optimal triplex vaccine strategy that promotes effective immune reconstitution with minimal CMV reactivation. All HCT-d will be vaccinated once with triplex, and all HCT-r will be boosted with 3 triplex injections on D28, 56, and 100. The initial open-label phase 1B segment will either have patients abstain from prevymis, or given 21D-100D of prophylaxis. The vaccination regimen with the least usage of prevymis that still results in no increase in reactivation compared to standard prevymis will be selected for follow-on randomized phase 2 segment of vaccination with reduced or no prevymis dosing compared to standard of care prevymis with no vaccination.

Transactions

Action Obligated Date
Amendment $646,643
Amendment $64,891
Amendment $584,019
Amendment $584,019
Amendment $616,432
Amendment $616,432
Amendment $616,432
Amendment $0
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Amendment $688,080
Amendment $688,080
Original award $688,080
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Subawards

Subrecipient Amount Awarded
Brigham & Womens Hospital Inc. In the proposed project we will provide Dr. Baden and his team both Triplex vaccine and placebo for his use in the two clinical trials described in the… $228,121
Northside Hospital, Inc. In the proposed project we will provide Dr. Solomon and his team both Triplex vaccine and placebo for his use in the two clinical trials described in the… $67,130

Quick answers

Who received award R01CA266783?

R01CA266783 was awarded to Beckman Research Institute Of The City Of Hope by National Cancer Institute (National Institutes of Health) on May 2, 2023.

How much is award R01CA266783 worth?

$5,793,108 has been obligated on R01CA266783.

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