A new breakthrough in CAR-T: the number of cells required for therapeutic benefit is reduced by 5 times, thanks to this protein

Over the past decade, CAR-T cell therapy has become increasingly common for refractory hematological malignancies
.
Despite these advances, a significant proportion of patients experience suboptimal CAR-T toxicity and persistence, which may lead to tumor cell escape and disease recurrence
.

The latest data presented at the EHA conference in June this year showed that Caribou Biosciences' allogeneic CAR-T, initially expected to treat non-Hodgkin's lymphoma, met this fate
.
Persistence of the product was questioned because half of the patients relapsed
.
Persistence has become an industry issue for allogeneic CAR-T developers, with Allogene, CRISPR Therapeutics and Precision Biosciences all seeing a large number of cancer patients relapse within 6 months of treatment
.
Caribou has removed the PD-1 receptor from its anti-CD19 product candidate, CB-010, to reduce CAR-T cell depletion and maintain high antitumor activity for a longer period of time
.

On June 13, researchers from Washington University in St.
Louis published an article in Nature Communications reporting that NeoImmuneTech's long-acting human IL-7 factor NT-17 combined with CAR-T therapy not only promoted CAR-T cell proliferation, but also increased Reduced cytotoxicity, reduced depletion and prolonged therapy durability
.
In vivo experiments in mice, the combination of the two significantly improved the efficacy of CAR-T therapy for acute myeloid leukemia and B-cell lymphoma, resulting in long-term tumor-free survival
.

NT-I7 (also known as efineptakin alfa, rhIL-7-hyFc) is an engineered dimeric IL-7 (hyFc:copyright:) fused to IgD and IgG4 elements that reduces complement activation while extending serum half-life in vivo , providing a clear pharmacological advantage for the short-lived natural recombinant human IL-7 (rhIL-7)
.

In a first-in-human trial in healthy volunteers (NCT02860715), a single intramuscular dose of NT-I7 (60 mcg/kg) resulted in a substantial increase in CD4+ and CD8+ T cell numbers, with no major adverse events or dose-limiting toxicities reported
.
Therefore, the researchers decided to explore the potential of this agent to enhance the activity of CAR-T cells
.

Studies have shown that NT-I7 can enhance the viability of CD19-targeted CAR-T cells and reduce their depletion in a mouse model of aggressive B-cell lymphoma, while promoting their expansion in the presence of CD19+ tumor cells
.
The combination of NT-17 and CD19-targeted CAR-T cells significantly shrank tumors in mice and prolonged the survival of mice compared with CAR-T cell therapy alone (bottom)
.

The combination of NT-17 and CD33-targeting CAR-T therapy has achieved similar effects in mice with acute myeloid leukemia
.

In addition, NT-17 can reduce the dose of CAR-T cell therapy required to provide survival benefit by enhancing the tumor-killing capacity of each CAR-T cell and promoting its expansion in vivo
.
In mouse models, in combination with NT-17, the effective dose of CAR-T therapy can be reduced by at least 5-fold (1.
25X106 cells to 2.
5X105 cells), while still achieving the same or even greater in vivo activity , and improve the durability of the therapy
.

Se Hwan Yang, Ph.
D.
, President and CEO of NeoImmuneTech, said: "These results demonstrate the broad applicability of NT-I7 in cell therapy.
In addition to its well-known benefits as long-acting human IL-7, NT-I7 has the ability to expand T Potential for cell subsets, boosting the immune system, and enhancing anticancer responses in patients with hematological and solid tumors
.
"

The next step for NeoImmuneTech is to see if NT-17 can have a similar effect in humans
.

References:

1# Immunity boosting treatment enhances CAR-T cell therapy for blood cancers (Source: Medical press)

2# Miriam Y.
Kim et al.
A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity.
Nature Communications.
(2022)

3# CAR-T countdown: NeoImmuneTech drug could reduce number of cells needed for cancer therapy fivefold (Source: FIERCE Biotech)

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