# A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity

**Authors:** Miriam Y. Kim, Reyka Jayasinghe, Jessica M. Devenport, Julie K. Ritchey, Michael P. Rettig, Julie O’Neal, Karl W. Staser, Krista M. Kennerly, Alun J. Carter, Feng Gao, Byung Ha Lee, Matthew L. Cooper, John F. DiPersio

PMC · DOI: 10.1038/s41467-022-30860-0 · Nature Communications · 2022-06-13

## TL;DR

A long-acting version of interleukin-7 boosts the effectiveness of CAR T cell therapy by improving cell expansion and anti-tumor activity.

## Contribution

A long-acting IL-7 fusion protein (rhIL-7-hyFc) is introduced as a novel adjuvant to enhance CAR T cell therapy.

## Key findings

- rhIL-7-hyFc promotes proliferation and persistence of human and murine CAR T cells in mouse models.
- The treatment leads to long-term tumor-free survival in tested models.
- rhIL-7-hyFc is proposed as a clinic-ready adjuvant for improving CAR T cell activity.

## Abstract

Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity.

Chimeric antigen receptor T cells represent a breakthrough treatment in hematologic malignancies, but insufficient level of cytotoxicity and persistence of T cells might compromise success. Authors show here that a recombinant long acting form of interleukin-7 enhances proliferation, persistence and cytotoxicity of the engineered T cells, resulting in long term disease remission.

## Linked entities

- **Species:** Homo sapiens (taxon 9606)

## Full-text entities

- **Genes:** Itga2 (integrin alpha 2) [NCBI Gene 16398] {aka CD49B, DX5, GPIa}, IL17F (interleukin 17F) [NCBI Gene 112744] {aka CANDF6, IL-17F, ML-1, ML1}, Itgam (integrin alpha M) [NCBI Gene 16409] {aka CD11b/CD18, CR3, CR3A, Cd11b, F730045J24Rik, Ly-40}, Il7 (interleukin 7) [NCBI Gene 16196] {aka A630026I06Rik, Il-7, hlb368}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, IL22 (interleukin 22) [NCBI Gene 50616] {aka IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL-23}, CCL3 (C-C motif chemokine ligand 3) [NCBI Gene 6348] {aka G0S19-1, LD78, LD78ALPHA, MIP-1-alpha, MIP1A, SCI}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, CD34 (CD34 molecule) [NCBI Gene 947], IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, GZMB (granzyme B) [NCBI Gene 3002] {aka C11, CCPI, CGL-1, CGL1, CSP-B, CSPB}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, IL7 (interleukin 7) [NCBI Gene 3574] {aka IL-7, IMD130}, Il15 (interleukin 15) [NCBI Gene 16168] {aka IL-15}, Sell (selectin, lymphocyte) [NCBI Gene 20343] {aka CD62L, L-selectin, LAM-1, LECAM-1, LECAM1, Lnhr}, Cd19 (CD19 antigen) [NCBI Gene 12478], SCFV (single-chain Fv fragment) [NCBI Gene 652070], NR1I3 (nuclear receptor subfamily 1 group I member 3) [NCBI Gene 9970] {aka CAR, CAR1, MB67}, Fcgr3 (Fc receptor, IgG, low affinity III) [NCBI Gene 14131] {aka CD16}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Ptprc (protein tyrosine phosphatase receptor type C) [NCBI Gene 19264] {aka B220, CD45R, Cd45, L-CA, Ly-5, Lyt-4}, Cd247 (CD247 antigen) [NCBI Gene 12503] {aka 4930549J05Rik, A430104F18Rik, Cd3, Cd3-eta, Cd3-zeta, Cd3h}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, IL21 (interleukin 21) [NCBI Gene 59067] {aka CVID11, IL-21, Za11}, Tigit (T cell immunoreceptor with Ig and ITIM domains) [NCBI Gene 100043314] {aka Vstm3}, CD33 (CD33 molecule) [NCBI Gene 945] {aka CD33rSiglec, SIGLEC-3, SIGLEC3, p67}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Cd8a (CD8 subunit alpha) [NCBI Gene 12525] {aka Ly-2, Ly-35, Ly-B, Lyt-2}, Cd44 (CD44 antigen) [NCBI Gene 12505] {aka HERMES, Ly-24, Pgp-1}, CCL11 (C-C motif chemokine ligand 11) [NCBI Gene 6356] {aka SCYA11}, CCL13 (C-C motif chemokine ligand 13) [NCBI Gene 6357] {aka CKb10, MCP-4, NCC-1, NCC1, SCYA13, SCYL1}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, Cd33 (CD33 molecule) [NCBI Gene 12489] {aka Siglec-3, gp67}, Havcr2 (hepatitis A virus cellular receptor 2) [NCBI Gene 171285] {aka TIM-3, Tim3, Timd3}, Gzmk (granzyme K) [NCBI Gene 14945], IL15 (interleukin 15) [NCBI Gene 3600] {aka IL-15}, CD19 (CD19 molecule) [NCBI Gene 930] {aka B4, CVID3}, CCR7 (C-C motif chemokine receptor 7) [NCBI Gene 1236] {aka BLR2, CC-CKR-7, CCR-7, CD197, CDw197, CMKBR7}, LTA (lymphotoxin alpha) [NCBI Gene 4049] {aka LT, TNFB, TNFSF1, TNLG1E}, CD28 (CD28 molecule) [NCBI Gene 940] {aka IMD123, Tp44}, Ly6g (lymphocyte antigen 6 family member G) [NCBI Gene 546644] {aka Gr-1, Gr1, Ly-6G}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, Cd244a (CD244 molecule A) [NCBI Gene 18106] {aka 2B4, C9.1, Cd244, F730046O15Rik, Ly90, NAIL}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 3627] {aka C7, IFI10, INP10, IP-10, SCYB10, crg-2}, TRAC (T cell receptor alpha constant) [NCBI Gene 28755] {aka IMD7, TCRA, TRCA}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, Nr1i3 (nuclear receptor subfamily 1, group I, member 3) [NCBI Gene 12355] {aka CAR, CAR-beta, Care2, ESTM32, MB67}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, Lag3 (lymphocyte-activation gene 3) [NCBI Gene 16768] {aka CD223, LAG-3, Ly66}, Trav6-3 (T cell receptor alpha variable 6-3) [NCBI Gene 328483] {aka Gm13948, Gm193, Gm4, TCR}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, Apc (APC, WNT signaling pathway regulator) [NCBI Gene 11789] {aka CC1, Min, mAPC}, Cd160 (CD160 antigen) [NCBI Gene 54215] {aka By55}, S100a4 (S100 calcium binding protein A4) [NCBI Gene 20198] {aka 18A2, 42a, Capl, FSp1, Mts1, PeL98}, Cd34 (CD34 antigen) [NCBI Gene 12490], IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Gzmb (granzyme B) [NCBI Gene 14939] {aka CCP-1/C11, CCP1, Ctla-1, Ctla1, GZB}
- **Diseases:** weight loss (MESH:D015431), thrombocytopenia (MESH:D013921), B cell aplasia (MESH:D015448), cervical dislocation (MESH:D002575), NOD (MESH:D020191), hematologic malignancies (MESH:D019337), Cancer (MESH:D009369), neurotoxicity (MESH:D020258), APL (MESH:D015473), asphyxiation (MESH:C537571), lethargy (MESH:D053609), RB (MESH:D012175), leukemia (MESH:D007938), lymphoma (MESH:D008223), cytotoxicity (MESH:D064420), AML (MESH:D015470), B-ALL (MESH:D015452), CRS (MESH:D000080424), paralysis (MESH:D010243), GVHD (MESH:D006086), leukocytosis (MESH:D007964), complement (MESH:D007153), B cell lymphoma (MESH:D016393)
- **Species:** Lentivirus (genus) [taxon 11646], Homo sapiens (human, species) [taxon 9606], Streptococcus pyogenes (species) [taxon 1314], Mus musculus (house mouse, species) [taxon 10090], Mycoplasma (genus) [taxon 2093]
- **Mutations:** H05H, glycine-serine
- **Cell lines:** UCART19 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_5989), Lenti-X 293T — Homo sapiens (Human), Transformed cell line (CVCL_4401), A20 tumor — Aedes aegypti (Yellowfever mosquito), Spontaneously immortalized cell line (CVCL_Z353), CRL-3273 — Homo sapiens (Human), Transformed cell line (CVCL_9P11), CCRF-CEM — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0207), Jurkat — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0065), CAR- — Mus musculus (Mouse), Transformed cell line (CVCL_WN86), U937 — Homo sapiens (Human), Adult acute monocytic leukemia, Cancer cell line (CVCL_0007), C57BL/ — Homo sapiens (Human), Burkitt lymphoma, Cancer cell line (CVCL_C152), Balb/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), CRL-1596 — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_B4FW), CRL-1593.2 — Homo sapiens (Human), Spina bifida, Finite cell line (CVCL_9G64), A20CBR — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_B2M9), pMD.Lg — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_B9IC), Ramos — Homo sapiens (Human), Burkitt lymphoma, Cancer cell line (CVCL_0597), TIB-208 — Mus musculus (Mouse), Hybridoma (CVCL_J866), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU), mCART19 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_B288), NALM6 — Homo sapiens (Human), Adult B acute lymphoblastic leukemia, Cancer cell line (CVCL_0092)

## Full text

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## Figures

8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC9192727/full.md

## References

39 references — full list in the complete paper: https://tomesphere.com/paper/PMC9192727/full.md

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Source: https://tomesphere.com/paper/PMC9192727