ll

Leading Edge

Commentary
Delivering the next generation of cancer
immunotherapies with RNA
Theresa M. Raimondo,1,2 Kaelan Reed,1,2 Dennis Shi,1,2 Robert Langer,1,2,3,4 and Daniel G. Anderson1,2,3,4,*
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
2David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
3Harvard–Massachusetts Institute of Technology, Division of Health Science and Technology, Massachusetts Institute of Technology,

Cambridge, MA 02142, USA

4Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

*Correspondence: dgander@mit.edu
https://doi.org/10.1016/j.cell.2023.02.031

Decades of oncologic clinical use have demonstrated that cancer immunotherapy provides unprecedented
therapeutic benefits. Tragically, only a minority of patients respond to existing immunotherapies. RNA lipid
nanoparticles have recently emerged as modular tools for immune stimulation. Here, we discuss advance-
ments in RNA-based cancer immunotherapies and opportunities for improvement.

INTRODUCTION and mRNA-based drugs and vaccines leucel-T, an autologous dendritic cell ther-
have validated their potential and opened apy for prostate cancer, was approved in
Immunotherapy is a key component of the door for expansion into new indica- 2010, yet never gained widespread use
modern cancer therapy, with more than tions. Research surrounding RNA-based owing to its high cost and underwhelming
40 monoclonal antibody therapeutics immunotherapies is broad, spanning clinical efficacy (NCT00065442). Recent
and 6 chimeric antigen receptor (CAR)-T RNA engineering to delivery technologies. advancements in our understanding of tu-
cell therapies now approved. Anti-PD1 Novel RNA constructs to amplify RNA mor immunology and vaccine platforms,
checkpoint inhibition, for example, has expression (e.g., self-amplifying RNA, however, have renewed the promise of
quadrupled 5-year survival rates for pa- circular RNA), modify translation (e.g., effective cancer vaccines.
tients with advanced non-small cell lung miRNA, siRNA), and gene editing (Cas9 Partially owing to their success in
cancer (KEYNOTE-001 trial). Despite the mRNA, single guide RNA [sgRNA]) curbing the COVID-19 pandemic, intra-
successful application of immunotherapy hold promise for next-generation cancer muscular mRNA lipid nanoparticle (LNP)
to a broad spectrum of malignancies, immunotherapy. Targeted delivery vehi- vaccines are one of the most promising
only a minority of cancer patients respond cles, including lipid and polymer nanopar- candidates for therapeutic cancer vac-
to existing immunotherapeutics, and ticles, cell or extracellular vesicle-based cines. A typical RNA LNP is composed
these therapeutics can have significant packaging, and hybrid systems, will likely of (1) ionizable or cationic lipids to interact
side effects. The need for, and optimism increase immunotherapy potency and with polyanionic RNA, (2) cholesterol
surrounding, new cancer immunother- decrease side effects. We believe that to adjust lipid-bilayer fluidity, (3) polyeth-
apies was highlighted by President Bi- substantial advancements in our under- ylene glycol (PEG)-lipids to assist in
den’s reignition of the Cancer Moonshot standing of cancer immunology, along particle stability, and (4) ‘‘helper’’ lipids,
funding on February 2, 2022 with the with our ability to identify personalized such as phospholipids. Together these
ambitious goal of cutting cancer death cancer antigens and develop RNA deliv- are formulated with RNA to form nano-
rates by 50% over the next 25 years. To ery vehicles, will all play central roles in particles on the order of
80–100 nm,
achieve this goal, translational immuno- next-generation immunotherapy. which protect the encapsulated RNA
therapy and overcoming resistance in from degradation and traffic it to the cyto-
non-responders were identified as 2 of mRNA nanoparticles for cancer plasm of target cells to allow for in vivo
10 central research recommendations. vaccines expression. The encapsulated mRNA
While many new immunotherapeutics Vaccination to promote therapeutic, anti- can encode for many proteins, including
will resemble those used today—anti- tumor immune responses has been a long- those conventionally difficult to express,
bodies, recombinant proteins, cell thera- time focus of cancer research. Unfortu- and its manufacturing is independent of
pies, and small molecules—we expect nately, challenges with the identification sequence.1 This inherent modularity of
the future will include new modalities, of tumor-specific and immunogenic neo- mRNA-LNP vaccines enables their formu-
particularly RNA therapeutics. Advance- antigens, effector cell recruitment, and lation and clinical translation more rapidly
ments in RNA chemistry and delivery are locally adjuvating immune cells in suppres- and economically than previous cell-
ushering in a new era of RNA-based sive tumor microenvironments have all his- based technologies.1 To date, COVID-19
immunotherapy. The approval of several torically hampered their clinical success.1 mRNA-LNP vaccines have been admin-
antisense, small interfering RNA (siRNA), The only approved cancer vaccine, Sipu- istered intramuscularly to billions of

Cell 186, April 13, 2023 ª 2023 Elsevier Inc. 1535

 ll
Commentary

patients with demonstrated safety and porating immune-stimulating RNA into response. Chemical approaches to
efficacy.2 The excitement surrounding vaccine formulations may combat improving LNP potency have been
mRNA vaccines is reflected in the clinical immunosuppressive tumor microenviron- explored extensively over the last decade
landscape—since 2021, 10 mRNA cancer ments and substantially improve thera- and typically include the development of
vaccine clinical trials have been initiated peutic efficacy. eTheRNA, for example, ionizable lipids to improve delivery and
(Table 1) (clinicaltrials.gov accessed on is exploring the addition of Tri-Mix the immunological response. While this
10/23/2022). mRNA—encoding caTLR4, CD40L, and approach has led to increased mRNA
A particularly exciting opportunity af- CD70—to cancer vaccines to enhance delivery, only a small percentage of the
forded by mRNA modularity is its use dendritic cell activation and antigen pre- dosed mRNA is processed by antigen-
in personalized, neoantigen vaccines sentation (Figure 1). Moderna has also presenting cells (APCs). Targeting mRNA
(Figure 1). Neoantigens are derived from shown that intratumoral administration of vaccines to lymphoid organ APCs, which
patient-specific tumor mutations that interleukin-23 (IL-23), IL-36g, and OX40L are capable of MHC-I cross-presentation
elicit an anti-tumor immune response.3 mRNA promotes type 1 helper T cell and CD8 T cell activation, may improve
Correctly selecting neoantigens, how- (Th1) transformation. Although not tested, vaccine potency. For example, BNT111,
ever, is non-trivial. Their selection requires this transformation may work synergisti- which is currently in phase II trials for
sequencing the patient’s tumor genome, cally with vaccines. Beyond mRNA, simul- melanoma (Table 1) and has promising
identifying mutations, and predicting taneous immune checkpoint silencing early results, utilizes a negatively charged
which mutations will lead to high-affinity (siRNA) may also prove therapeutic. Novel formulation that reportedly facilitates
major histocompatibility complex (MHC)- combination therapies may bring cost re- specific uptake in both macrophage and
binding neoantigen peptides.3 The ability ductions in addition to therapeutic dendritic APCs. Beyond charge-based
to in vitro transcribe mRNA encoding pa- benefits. targeting, ligand conjugation to LNP sur-
tient-specific neoantigens directly from faces (e.g., anti-CD11c or DEC205 anti-
sequencing data without ex vivo cell cul- Improving next-generation mRNA bodies) may also improve APC targeting.
ture or protein engineering renders this cancer vaccines It is possible that targeting, together
platform particularly useful for neoantigen We believe opportunities for mRNA can- with the development of more potent
vaccination. Further, multiple neoanti- cer vaccine improvement fall broadly LNPs, may facilitate enhanced immune
gens can be encoded by a single mRNA, into at least three categories: (1) responses at lower RNA doses.
increasing vaccine breadth and potency. increasing the number of patients treat- The third challenge, improving mRNA
The majority of (6/10) mRNA cancer vac- able with cancer vaccines, (2) improving cancer vaccine tolerability, is likely the
cine trials initiated since 2021 will explore potency of RNA-LNPs, and (3) improving least impactful. When compared with
patient-specific antigens (Table 1), and their tolerability. To address the first, a conventional flu vaccines, SARS-CoV-2
preliminary trials have shown promise. better understanding of how to design an- mRNA vaccines have similar or better
Sahin et al. reported phase I results tigens for a broader range of cancers and clinical safety,6 though improved tolera-
wherein melanoma patients were vacci- patients is needed. Many clinical trials bility may still be worthy of study. Like all
nated with mRNA encoding up to 10 neo- have focused on melanoma, as its high vaccines, dose-limiting studies reveal
antigens. CD4 and CD8 T cell responses mutation rate increases the number of the possibility of flu-like symptoms, fever,
against multiple neoantigens were neoantigens and therefore the likelihood headaches, and chills.7 Additionally,
observed in all patients along with a signif- of identifying one that elicits an effective intravenous infusions of nanoparticles,
icant reduction in metastasis.4 Excitingly, immune response. Extension to lower utilized for some cancer vaccines, may
recent results from a phase 2b trial mutational burden cancers may require also lead to shorter-term, allergy-like infu-
(NCT03897881) mark the first demonstra- additional tools to improve antigen sion-related reactions (IRRs). However, in
tion of mRNA-neoantigen therapeutic effi- design. Advancements in neural networks the context of treating cancer, these side
cacy in a randomized clinical trial. In this and deep learning may be particularly effects must be weighed against the
trial, a mRNA vaccine encoding 34 pa- helpful, as they utilize multiple data sour- clinically important efficacy they have
tient-specific neoantigens, in combina- ces to predict optimal antigen designs.5 shown in early human studies, with a
tion with anti-PD1 (KEYTRUDA), reduced EDGE, for example, is a recent deep- 42% reduction in death or relapse in the
the risk of recurrence or death by 44% learning approach that predicts peptide recently reported Merck-Moderna trial,
compared with KEYTRUDA alone in pa- MHC-I binding using mass spectrometry, where patients were treated intramuscu-
tients with resected stage III/IV melanoma DNA, and RNA sequencing.5 Unfortu- larly every 3 weeks.
at high risk of recurrence. Moderna and nately, the utility of such deep-learning Identifying sources of mRNA-LNP reac-
Merck plan to initiate a phase 3 study in models is hindered by small sample togenicity, however, is difficult, as animal
2023. The ability to develop patient- sizes and inconsistent data generation.3 models do not accurately recapitulate
specific vaccines has the potential to elicit Large, high-quality cancer neoantigen human symptoms, and symptom severity
therapeutic responses in those recalci- datasets would greatly improve the utility is highly variable. Despite this, recent
trant to existing treatments. of these tools. studies offer insight into the biological
Beyond personalizing vaccine anti- The second challenge, improving RNA- mechanisms regulating reactogenicity.
gens, RNA affords a unique opportunity LNP potency, is important for enhancing Exogenous mRNA can be immunostimu-
to develop combination therapies. Incor- CD8 T cell activation and anti-tumor latory, as it can be recognized by pattern

1536 Cell 186, April 13, 2023

 Commentary
Table 1. mRNA cancer vaccine Clinical Trails initiated since 1/2021
NCT number Conditions Status Vaccine Additional interventions Phase Sponsor
NCT05192460 Gastric cancer Recruiting Personalized neoantigen PD-1/L1 NA jianming xu/NeoCura/The Affiliated
Esophageal cancer tumor vaccine (PGV002 Hospital of the Chinese Academy
Liver cancer mRNA vaccine) of Military Medical Sciences
NCT05202561 Advanced solid tumor with Recruiting RNA tumor vaccine PD-1 inhibitor (Navuliumab) I First Affiliated Hospital
KRAS mutation Bengbu Medical College
NCT04534205 Unresectable head and neck Recruiting hpv16 e6/7 mrna Anti-PD1 (Pembrolizumab) II BioNTech SE
squamous cell carcinoma vaccine (BNT113)
Metastatic head and neck cancer
Recurrent head and neck cancer
NCT05456165 Colonic neoplasms Recruiting patient-specific Anti-PDL1 (Atezolizumab) II Gritstone bio, Inc.
Colorectal neoplasms neoantigen vaccine Anti-CTLA4 (Ipilimumab)
(GRT-C901; GRT-R902) Adjuvant chemotherapy
NCT05141721 Colorectal neoplasms Recruiting patient-specific neoantigen Anti-PDL1 (Atezolizumab) II/III Gritstone bio, Inc.
vaccine (GRT-C901; Anti-CTLA4 (Ipilimumab)
GRT-R902) anti-angiogenic (Bevacizumab)
Chemotherapy (Fluoropyrimidine,
Oxaliplatin)
NCT05198752 Solid tumors Recruiting patient-specific none I Stemirna Therapeutics
neoantigen vaccine
(SW1115C3)
NCT04526899 Melanoma stage III/IV Recruiting 4 - shared antigen, Anti-PD1 (Cemiplimab) II BioNTech SE
Unresectable melanoma mRNA-lipoplex (BNT111)
NCT04486378 Colorectal cancer stage II/III Recruiting patient-specific none II BioNTech SE
neoantigens (BNT122)
NCT04573140 Pediatric high-grade gliomas Recruiting RNA-lipid particles none I University of Florida
Adult glioblastoma (RNA-LP) loaded with
autologous total tumor
mRNA, + lysosomal
associated membrane
Cell 186, April 13, 2023 1537

protein (LAMP) mRNA

NCT04963413 Glioblastoma Recruiting Autologous DCs loaded GM-CSF I University of Florida/Immunomic
with RNA encoding the Therapeutics, Inc.
human CMV matrix
protein pp65-flLAMP

ll
 ll
Commentary

routes of vaccine administration (e.g.,

nasal, oral). Timing and location (local
vs. systemic) of immune activation may
determine if the outcome is damaging or
protective. Nuanced engineering will be
required to design vaccines that minimize
activation of counterproductive innate
immune reactions while still promoting
APC maturation, antigen presentation,
and adaptive immunity.

Targeted RNA delivery for in vivo

CAR therapy
The clinical approval of CAR-T therapies
represents a step-change improvement
in blood cancer treatment. Approved
CAR therapies are autologous cell thera-
pies wherein T cells are engineered
ex vivo to express CARs against cancer
antigen. The recent phase 1b/2 trial CAR-
TITUDE-1 for the treatment of refractory
adult multiple myeloma achieved a 97%
objective response rate. This remarkable
data resulted in U.S. Food and Drug
Administration (FDA) approval of Jans-
sen’s Carvykti in 2022, the sixth CAR-T
FDA approval in just five years. Despite
their effectiveness, CAR-T clinical use
is hindered by exceptionally high costs
and poor cell availability—Carvykti costs
Figure 1. RNA lipid nanoparticles (LNPs) are modular tools that can be engineered to pre- $465,000 per treatment. Costs are
cisely tune immune responses
(Center box) Various RNAs can be encapsulated in LNPs. Single-stranded mRNA (red) and double-
partially due to complex manufacturing
stranded siRNA (yellow) can encode cancer vaccine antigens and knock down checkpoint inhibitors, and lengthy timelines required to (1) har-
respectively. Circular RNA (gray), engineered to eliminate 30 and 50 ends, can enhance expression dura- vest patient-derived T cells, (2) expand
tion, which may be beneficial for both vaccine antigens and in vivo CAR generation. (Tan quadrant) Deep and gene-edit T cells ex vivo, and (3) re-
learning is applied to sequencing data from patient biopsies to predict unique cancer neoantigens, which
are then encoded in mRNA. (Green quadrant) Combined delivery of antigen-encoding with cytokine-en- infuse edited cells back into lymphode-
coding mRNA, such as Tri-Mix, can enhance antigen presentation by dendritic cells (DCs). (Blue half) Lipid pleted patients. Expanding accessibility
structures, LNP formulation parameters, PEG lipids, and the conjugation of antibodies can all be en- to CAR therapies will require innovative
gineered to increase the cell specificity of LNPs in vivo. Targeted in vivo LNP delivery will be important for
in vivo generation of CAR T cells and macrophages.
approaches with simplified processing.
In vivo RNA delivery to T cells is an
attractive approach. CAR mRNA encap-
recognition receptors (PRRs) on APCs. stantial gaps in our understanding of how sulated into cell type-specific, i.e., T cell,
Tahtinen et al. identified the IL-1/IL-1ra both LNP design and genetic/environ- nanoparticles would be an ‘‘off-the-shelf’’
inflammatory axis as a key regulator mental factors affect mRNA vaccine treatment (Figure 1). Such in vivo mRNA-
of post-vaccination flu-like symptoms, reactogenicity. Importantly, activation of LNP-based CAR-T generation may bring
though the exact mechanism of IL-1 stim- such inflammatory pathways and type I therapeutic and safety benefits in addition
ulation remains unknown.8 Type I inter- interferon can ultimately inhibit vaccine to time and cost advantages. LNP mRNA
feron induction by TLR3/7/8 and RIG-1 mRNA translation, thereby inhibiting anti- delivery mitigates concerns of insertional
recognition of unmodified mRNA may gen expression and dampening immunity. mutagenesis associated with lentiviral
also play a role; however, there are con- Mitigation of these inflammatory pro- vectors used in existing CAR-T therapies.
flicting reports on the extent of immune cesses may therefore improve vaccine Further, the transient nature of mRNA
activation by both modified and unmodi- potency as well as side effects. Possible expression would enable adjustment of
fied mRNA. IRRs to nanomaterials, remedies include the alteration or CAR-T levels through dosing, which may
meanwhile, are thought to be primarily replacement of certain LNP components, reduce toxicity compared with approved
caused by complement activation-related incorporation of stealth lipids to avoid im- therapies. Finally, in vivo CAR-T genera-
pseudoallergy (CARPA).9 Although these mune surveillance,10 RNA modifications tion may preclude the need for lymphode-
studies provide insight, there remain sub- to minimize PRR recognition, and other pletion, which has many undesirable side

1538 Cell 186, April 13, 2023

 ll
Commentary

effects. If realized, in vivo CAR-T genera- profile, it also results in CAR presentation IRRs are observed in up to 20% of pa-
tion would revolutionize the field. loss within one week.11 This loss of CAR tients and necessitate pretreatment 6 h
Recent advancements in LNP T cell tar- expression can lead to relapse upon before infusion with a combination of ste-
geting have laid the groundwork for in vivo treatment cessation.11 Thus, CAR mRNA roids (dexamethasone), antihistamines
CAR-T. Parayath et al. showed that sys- nanoparticles may require repeated (diphenhydramine, ranitidine), and antipy-
temic administration of polymeric nano- administration. As in cancer vaccines, retics (acetaminophen). The need for
particles decorated with CD8 antibodies however, side effects associated with immunosuppression prior to the higher
resulted in CAR expression in 10% of RNA-LNPs limit redosing. Increasing doses utilized in systemic infusion, as
CD8 T cells in a murine leukemia model.11 CAR expression duration would therefore compared with local administration, of
This level of CAR expression achieved be beneficial. RNA-LNPs is an underappreciated chal-
comparable therapeutic efficacy with One approach to increasing expression lenge, as immunotherapies require some
ex vivo edited T cells.11 Although this duration is the use of circular mRNA. immune function. Thus, patients who
study demonstrated the therapeutic po- Without ends, it is resistant to exonu- experience substantial IRRs to intrave-
tential of in vivo CAR-T, clinical challenges clease degradation and decapping, nous RNA-LNPs may be prevented from
remain. which can result in extended expression receiving these therapies. Preclinical
Perhaps the most significant challenge compared with linear mRNA.12 Alterna- in vivo CAR studies typically require
is increasing LNP specificity. Recent pub- tively, the LNP itself can be tuned. Mod- high systemic doses. Parayath et al., for
lications have demonstrated potential erna recently reported an LNP with a example, administered 50 mg mRNA/
T cell targeting via conjugation of T cell- nearly 6-fold increase in expression dura- week intravenously, equivalent to a
surface receptor ligands (e.g., antibodies tion compared with existing LNPs.13 We human dose of
0.16 mg/kg/week.11
against CD3/4/5/8) onto mRNA-LNPs. are optimistic that advancements in both Comparatively, intramuscular cancer
Both covalent and electrostatic adsorp- RNA design and delivery will improve the vaccines have shown promising clinical
tion of targeting antibodies have been potency and therapeutic duration of results at doses on the order of
used successfully, preclinically. Strate- transfected cells, thus enabling in vivo 0.001 mg/kg, although Moderna has
gies to improve conjugation efficiency CAR-T therapy. administered cancer vaccines at doses
and control ligand orientation, as well as up to 1 mg intramuscularly in phase 1
more precise engineering of the targeting Extension of in vivo CAR therapy trials, and BioNTech has explored intra-
ligand, may improve LNP potency. Bio- beyond T cells venous vaccine administration. Novel
logical approaches, including site-spe- Design principles for specificity, dura- formulations and RNA modifications to
cific enzyme-mediated reactions and bility, and tolerability may be applied to further reduce RNA-LNP reactogenicity
ligand post-insertion into LNPs, are active target RNA delivery to other immune cells are therefore of considerable importance
areas of research. Importantly, targeting for diverse therapeutic purposes. For for therapeutic success.
ligands enable both T cell homing and instance, targeting CAR mRNA to macro- Developing less reactogenic RNA-
LNP internalization via receptor-mediated phages could facilitate the development LNPs will require improved understand-
endocytosis, thereby enhancing transfec- of CAR therapies for solid tumors, an ing. Better insight into the biologic factors
tion in hard-to-transfect T cells. However, area existing CAR-T cannot address. Un- mediating adverse responses may be re-
to date, preclinical studies with antibody- like T cells, macrophages are abundant in vealed by screening patients who were
targeted LNPs have also shown off-target many solid tumors, comprising up to 50% particularly sensitive to COVID-19 vac-
delivery to hepatocytes and macro- of the immune cell infiltrate.14 As phago- cines. With potentially millions of human-
phages due to opsonization by serum cytes, macrophage delivery of CAR derived data points, this may offer insight
proteins, which compete with nanopar- LNPs may be much easier relative to into common features of mRNA-LNP
ticle-conjugated ligands. T cells. Carisma Therapeutics demon- sensitivity. We are hopeful that continued
Improving T cell specificity and trans- strated the ability of CAR macrophages, development of lipids and LNP formula-
fection efficiency will require innovative directed against HER2, to phagocytose tions will improve both potency and reac-
engineering. Approved LNPs have a xenografted SKOV3 cancer cells, present togenicity to yield mRNA therapies with
modest half-life. Ligand-mediated T cell antigens, and re-model the tumor micro- increased therapeutic windows. Kranz
delivery may require improved ‘‘stealth’’ environment.15 Carisma and Moderna et al. demonstrated that by altering nano-
properties to resist delivery to off-target have since partnered to utilize mRNA- particle charge, dendritic cells were tar-
tissues. However, while increasing PEG- LNPs to target monocyte/macrophages geted, type I interferon-dependent immu-
lipid content can lengthen LNP circulation in vivo for CAR expression. nity was induced, and antigen-specific
half-life, it can also lead to reduced endo- T cell responses were observed in mela-
somal escape and mRNA expression.10 Challenges with high-dose noma patients (NCT02410733). There is
Balancing these factors will require new intravenous RNA-LNP therapy a vast, unexplored chemical space avail-
approaches to LNP design. Clinically approved intravenous RNA- able for LNP structure, as well as other
CAR expression duration may also LNP therapies typically require premedi- types of RNA nanoformulations, and with
affect clinical potency of in vivo mRNA cation with immune suppressants. For an increased focus on reactogenicity, it
CAR-T therapies. While the transient na- example, according to the FDA drug label should be possible to identify improved
ture of mRNA provides a beneficial safety for Onpattro, an intravenous siRNA-LNP, RNA-LNP designs.

Cell 186, April 13, 2023 1539

 ll
Commentary

Conclusion apies. Nat. Biotechnol. 40, 840–854. https:// Nat. Immunol. 23, 532–542. https://doi.org/
The tremendous success of immuno- doi.org/10.1038/s41587-022-01294-2. 10.1038/s41590-022-01160-y.
therapy has demonstrated that the im- 2. Xu, K., Dai, L., and Gao, G.F. (2021). Humoral 9. Kozma, G.T., Mészáros, T., Vashegyi, I., Fülöp,
mune system remains one of our most and cellular immunity and the safety of T., Örfi, E., Dézsi, L., Rosivall, L., Bavli, Y., Ur-
powerful tools against cancer. How- COVID-19 vaccines: a summary of data banics, R., Mollnes, T.E., et al. (2019). Pseudo-
published by 21 May 2021. Int. Immunol. anaphylaxis to polyethylene glycol (PEG)-
ever, many patients do not respond
33, 529–540. https://doi.org/10.1093/INTIMM/ coated liposomes: roles of anti-PEG IgM and
to existing drugs, emphasizing the need DXAB061. complement activation in a porcine model
for advancements. Improved anti-cancer of human infusion reactions. ACS Nano 13,
3. Lang, F., Schrörs, B., Löwer, M., Türeci, Ö.,
immune responses will require the 9315–9324. https://doi.org/10.1021/acsnano.
and Sahin, U. (2022). Identification of neoanti-
concerted effort of researchers and clini- gens for individualized therapeutic cancer vac-
9b03942.
cians to advance our understanding of tu- cines. Nat. Rev. Drug Discov. 21, 261–282. 10. Hald Albertsen, C., Kulkarni, J.A., Witzigmann,
mor immunology, novel therapeutic mo- https://doi.org/10.1038/s41573-021-00387-y. D., Lind, M., Petersson, K., and Simonsen, J.B.
dalities, and methods of delivery. RNA 4. Sahin, U., Derhovanessian, E., Miller, M.,
(2022). The role of lipid components in lipid
therapeutics have an inherent ability to nanoparticles for vaccines and gene therapy.
Kloke, B.P., Simon, P., Löwer, M., Bukur, V.,
target specific genes, induce immune Adv. Drug Deliv. Rev. 188, 114416. https://
Tadmor, A.D., Luxemburger, U., Schrörs, B.,
doi.org/10.1016/j.addr.2022.114416.
activation, and are readily delivered in vivo et al. (2017). Personalized RNA mutanome
via targeted nanoparticles. While chal- vaccines mobilize poly-specific therapeutic 11. Parayath, N.N., Stephan, S.B., Koehne, A.L.,
lenges remain to the development of immunity against cancer. Nature 547, 222– Nelson, P.S., and Stephan, M.T. (2020). In vi-
226. https://doi.org/10.1038/nature23003. tro-transcribed antigen receptor mRNA nano-
safe and effective RNA delivery systems,
carriers for transient expression in circulating
we believe that RNA nanotechnologies 5. Bulik-Sullivan, B., Busby, J., Palmer, C.D., Da-
T cells in vivo. Nat. Commun. 11, 6080.
will ultimately be important components vis, M.J., Murphy, T., Clark, A., Busby, M.,
https://doi.org/10.1038/s41467-020-19486-2.
Duke, F., Yang, A., Young, L., et al. (2018).
of next-generation immunotherapies.
Deep learning using tumor HLA peptide mass 12. Wesselhoeft, R.A., Kowalski, P.S., and Ander-
spectrometry datasets improves neoantigen son, D.G. (2018). Engineering circular RNA for
ACKNOWLEDGMENTS
identification. Nat. Biotechnol. 37, 55–63. potent and stable translation in eukaryotic
https://doi.org/10.1038/nbt.4313. cells. Nat. Commun. 9, 2629. https://doi.org/
This work was supported by FUJIFILM, Translate
10.1038/s41467-018-05096-6.
Bio, the NIH (grant nos. R61 AI161805 and R01 6. Kim, M.S., Jung, S.Y., Ahn, J.G., Park, S.J.,
HL162564-02), and the Marble Center for Cancer Shoenfeld, Y., Kronbichler, A., Koyanagi, A., 13. Cornebise, M., Narayanan, E., Xia, Y., Acosta,
Nanomedicine and Cancer Center Support (core) Dragioti, E., Tizaoui, K., Hong, S.H., et al. E., Ci, L., Koch, H., Milton, J., Sabnis, S., Sale-
grant P30-CA14051 from the National Cancer (2022). Comparative safety of mRNA COVID- rno, T., Benenato, K.E., et al. (2021). Discovery
Institute. 19 vaccines to influenza vaccines: A pharma- of a novel amino lipid that improves lipid
covigilance analysis using WHO international nanoparticle performance through specific in-
DECLARATION OF INTERESTS database. J. Med. Virol. 94, 1085–1095. teractions with mRNA. Adv. Funct. Materials
https://doi.org/10.1002/JMV.27424. 32, 2106727. https://doi.org/10.1002/ADFM.
D.G.A. is a founder of CRISPR Tx, ORNA Tx, and 202106727.
7. Jackson, L.A., Anderson, E.J., Rouphael, N.G.,
performs sponsored research with Sanofi-Aventis.
Roberts, P.C., Makhene, M., Coler, R.N., 14. Cassetta, L., and Pollard, J.W. (2018). Target-
R.L. is a founder of Moderna. For a list of entities
McCullough, M.P., Chappell, J.D., Denison, ing macrophages: therapeutic approaches in
with which R.L. is involved, compensated or
M.R., Stevens, L.J., et al. (2020). An mRNA cancer. Nat. Rev. Drug Discov. 17, 887–904.
uncompensated, see https://www.dropbox.com/
vaccine against SARS-CoV-2 — Preliminary https://doi.org/10.1038/nrd.2018.169.
s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf
Report. N. Engl. J. Med. 383, 1920–1931.
?dl=0. 15. Klichinsky, M., Ruella, M., Shestova, O., Lu,
https://doi.org/10.1056/NEJMoa2022483.
X.M., Best, A., Zeeman, M., Schmierer, M.,
REFERENCES 8. Tahtinen, S., Tong, A.J., Himmels, P., Oh, J., Gabrusiewicz, K., Anderson, N.R., Petty, N.E.,
Paler-Martinez, A., Kim, L., Wichner, S., Oei, et al. (2020). Human chimeric antigen receptor
1. Barbier, A.J., Jiang, A.Y., Zhang, P., Wooster, Y., McCarron, M.J., Freund, E.C., et al. macrophages for cancer immunotherapy. Nat.
R., and Anderson, D.G. (2022). The clinical (2022). IL-1 and IL-1ra are key regulators of Biotechnol. 38, 947–953. https://doi.org/10.
progress of mRNA vaccines and immunother- the inflammatory response to RNA vaccines. 1038/s41587-020-0462-y.

1540 Cell 186, April 13, 2023