Page 34 - Science

INSIGHTS | PERSPECTIVES

IMMUNOTHERAPY
Engineering a designer immunotherapy

Tailoring cytokine selectivity by engineering receptor-ligand pairs circumvents toxicity

By Crystal L. Mackall induce profound capillary leakage syndrome, IL-2 with high affinity. OrthoIL-2Rb retained
presumably related to IL-2 signaling in en- normal interactions with IL-2Rg, the subunit
nderstanding of the human immune dothelial cells (7, 8). Furthermore, although essential for transmitting the IL-2 signal via
system has fueled development of rhIL-2 induces the expansion of activated phosphorylated signal transducer and activa-
numerous drugs, categorized as bio- effector T cells and natural killer (NK) cells, tor of transcription 5 (STAT5) (see the figure).
logics, designed to mimic or inhibit both desirable for antitumor immunity, the The authors also randomly mutagenized IL-2
natural immune responses. Recently, agent also expands regulatory T cells (T ) and selected two orthoIL-2s that selectively
regs
U immunoengineering has emerged as (9), which inhibit antitumor immunity. bound orthoIL-2Rb. 3A10 was truly orthogo-
a distinct discipline aimed at creating in- Sockolosky et al. sought to harness the nal as it showed no binding to natural IL-2Rb
creasingly sophisticated therapeutics that benefits of IL-2 for cancer immunotherapy, yet bound orthoIL-2Rb, albeit with reduced
can tailor immune responses for increased while avoiding the toxicity and undesirable affinity compared to native IL-2–IL-2Rb
potency and/or diminished tox- interactions. Conversely, 1G12
icity. On page 1037 of this issue, showed high affinity for orthoIL-
Sockolosky et al. (1) test the OrthoIL-2 signaling expands tumor-reactive T cells 2Rb but also bound native IL-
hypothesis that an engineered Sockolosky et al. generated orthoIL-2 to selectively bind orthoIL-2Rb and induce 2Rb with low affinity.
interleukin-2 (IL-2)–IL-2 recep- STAT5 phosphorylation (P). Adoptive transfer of tumor-specific T cells genetically In a model of adoptive T cell Downloaded from
tor-b (IL-2Rb) pair can expand engineered to express orthoIL-2Rb, followed by treatment with orthoIL-2, resulted immunotherapy for melanoma,
effector T cells for cancer im- in selective expansion of tumor-specific T cells in vivo without affecting NK cells they administered orthoIL-2 to
munotherapy while avoiding and T regs and without IL-2–associated toxicity from signaling on endothelial cells. mice that received infusions
the toxicities associated with of transgenic T cells that rec-
administration of natural IL-2. IL-2Ra ognize a peptide expressed by
OrthoIL-2Rb
Immunoengineering has dem- T cell the melanoma cells. Prior to
onstrated remarkable clinical receptor infusion, the transgenic T cells
IL-2Rg
success. In 2017, the U.S. Food and STAT5-P OrthoIL-2 were genetically engineered to http://science.sciencemag.org/
Drug Administration (FDA) ap- express orthoIL-2Rb, but they
proved blinatumomab, a bispe- Native also retained expression of the
IL-2Rb
cific antibody that binds CD19, natural IL-2R. Both orthoIL-2s
which is expressed on acute lym- selectively expanded orthoIL-
phoblastic leukemia (ALL) cells, 2Rb–expressing transgenic T
and binds CD3 on resident, but Tumor cell Adoptively transferred cells in vivo, but the magnitude
antigen-nonspecific, T cells, re- tumor-specifc T cell IL-2 of the effect was greater with
sulting in T cell killing of ALL 3A10, despite low-affinity bind- on March 1, 2018
cells and improved clinical out- ing, presumably due to the lack
comes (2). Additionally, the FDA of competition by cells express-
approved tisagenlecleucel and ing natural IL-2Rb. Similarly,
axicabtagene ciloleucel, engi- 3A10 administration was non-
neered T cells expressing chime- toxic, whereas 1G12 induced the
ric antigen receptors that merge generalized toxicity previously
monoclonal antibody binding NK cell Endothelial cell T cell described with rhIL-2 therapy.
reg
domains with T cell signaling Importantly, both orthoIL-2s
endodomains to induce potent antitumor ef- expansion of T , by engineering an or- induced antitumor effects in the mice that
regs
fects in tumors expressing the CD19 antigen thogonal IL-2 and IL-2Rb pair. Orthogonal- were equivalent to those of native IL-2.
(3–5). Both of these agents mediate impres- ity, a term originally used in mathematics These results have the potential for broad
sive clinical activity but are associated with to describe perpendicular vectors that are clinical application because they provide con-
considerable toxicities related to excessive therefore nonintersecting, has evolved to vincing evidence that an orthogonal cytokine
cytokine production (6). also generally describe relationships that are system can be designed and implemented for
Recombinant human IL-2 (rhIL-2) is an statistically independent, partitioned, or iso- therapeutic effect in cancer immunotherapy.
FDA-approved biologic for the treatment of lated. Thus, orthogonal receptor–ligand pairs The results pave the way for testing adoptive
renal cell carcinoma and malignant mela- are restricted to exclusively signal together. cell therapy using tumor-specific T cells ge-
noma. However, its clinical impact has been Working in a mouse model and guided by netically engineered to express orthoIL-2Rb.
limited because the doses of rhIL-2 required structural knowledge of IL-2–IL-2Rb binding, The system could also eliminate the need
for clinically meaningful antitumor effects the authors created orthoIL-2Rb, a mutant for lymphodepletion in patients receiving
with two amino acid substitutions rendering adoptive cell therapy for cancer. Numerous GRAPHIC: A. KITTERMAN/SCIENCE
it unable to bind natural IL-2. This property studies have demonstrated that adoptively
Department of Pediatrics and Medicine, and Stanford Cancer
Institute, 265 Campus Way, G3141A, Stanford University, was independent of IL-2Ra, a nonsignaling transferred T cells do not substantially ex-
Stanford, CA, USA. Email: cmackall@stanford.edu component of the IL-2R complex that binds pand in vivo unless patients are first treated

990 2 MARCH 2018 • VOL 359 ISSUE 6379 sciencemag.org SCIENCE
Published by AAAS

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