Cell2015-Immunotherapy The Path to Win the War

Leading Edge

Voices

Immunotherapy:The Path to Win the War on Cancer?

On Breakthroughs and

Evolution

Suzanne L.Topalian

Johns Hopkins Kimmel Cancer Center

Drugs targeting immune checkpoint mole-cules such as CTLA-4,PD-1,and PD-L1 are being heralded as a breakthrough in oncology.However,‘‘breakthrough’’is a misnomer belying several decades of basic immunology advances and clinical trial and error leading up to this point.It was only after basic science uncovered the protean pathways restraining anti-tumor immunity that we could begin to unravel how to subvert them.The broad activity spectrum of PD-1pathway blockers against multiple cancer types has validated this as a‘‘common denomi-nator’’treatment approach and dispels the perception that‘‘immunogenic’’cancers are anomalies.We are now challenged to understand immune resistance mecha-nisms utilized by‘‘non-responsive’’tumor types(e.g.,prostate cancer)as well as the50%or more of individuals with ‘‘responsive’’tumor types who do not bene?t from these drugs.Identifying collateral pathways for co-targeting in combination treatment regimens requires an intellectual leap to consider unex-pected intersections between the immune system and genetics,epigenetics,and metabolism.For instance,tumor muta-tional density,a surrogate indicator of neo-antigens available for immune recognition, correlates with the responsiveness of mel-anoma to anti-CTLA-4,and lung cancer to anti-PD-1.In the?nal analysis,teamwork with cross-fertilization of ideas across different scienti?c disciplines has driven the evolution to today’s‘‘breakthroughs’’and will meet tomorrow’s challenges.Central Dogma for

Immunotherapy

Jedd D.Wolchok and Timothy A.Chan

Memorial Sloan Kettering Cancer Center

In biology classes,we learned about the

central dogma of molecular biology—

DNA makes RNA and RNA makes protein.

We’ve also learned about factors that

regulate this central process,such as the

in?uence of epigenetics,micro-RNAs,

and mechanisms regulating post-tran-

scriptional and translational control.

Despite the?ne intricacies,the central

dogma of molecular biology remains

intact—inherently elegant and graspable.

A unifying concept for cancer immu-

nology,on the other hand,has remained

elusive until recently.We now have discov-

ered the existence of molecular mecha-

nisms of immune surveillance(thanks to

Bob Schreiber)and that the number and

quality of immune cells within the tumor

microenvironment has signi?cant prog-

nostic impact in a variety of cancers.The

quantity and quality of so-called‘‘passen-

ger’’mutations in the tumor are also very

important in determining the likelihood

of success of immunologic checkpoint

blockade with CTLA-4or PD-1pathway

blocking antibodies.A putative dogma

therefore is that mutations drive baseline

immune reactivity and baseline immune

reactivity is what determines the potential

for bene?t of immune potentiating thera-

pies.As in molecular biology,there are

likely to be modi?ers,such as inhibitory

cells populations,hostile microenviron-

ments,and loss of antigen presenting

capacity.Yet,a unifying concept will

likely allow the?eld to further re?ne its

approaches and speci?cally address the

immunologic needs of individual patients.

Not Just Another

Hallmark

Ira Mellman

Genentech

After an incubation period of nearly

100years,cancer immunotherapy has

emerged as a transformative approach

to treat a wide variety of cancers.

Although still early days,immunotherapy

provides a degree of sustained clinical

bene?t rarely observed with more tradi-

tional cancer treatments.The excitement

is,therefore,being largely driven by

clinical results rather than by‘‘break-

throughs’’in the laboratory.There are

nevertheless two daunting challenges.

First,the?eld has progressed so rapidly

in the clinic that our understanding of

the underlying basic science and mecha-

nisms of action are remarkably thin.

Second,the tools we have to assess

mechanism and correlates of treatment

response(or lack thereof)remain rudi-

mentary.Meeting these challenges is crit-

ical,since only a minority of patients

as yet exhibit maximal bene?t from immu-

notherapy.Importantly,clinical responses

to agents such as anti-PD-L1/PD-1are

often clear and dramatic,thereby creating

the opportunity to discover biomarkers

and use them to understand inevitable

patient to patient variations.Exploiting

these correlates of clinical response will

provide insights into basic cancer biology

and inform immunotherapy combinations

that can be expected to result in higher

response rates and disease cures.Our

task will be to back?ll the science behind

an exciting and validated therapeutic

approach,ensuring that the?eld can

look forward to a very exciting next

decade both in the lab and in the clinic.

Cell161,April9,2015a2015Elsevier Inc.185

New Trends in Cancer

Vaccines

Karolina Palucka and Jacques Banchereau The Jackson Laboratory for Genomic Medicine Clinical responses to checkpoint blockade are linked to the presence of T cell immunity to cancer-speci?c muta-tions.One way to increase the rate of clinical responses is to use vaccination to expand T cells speci?c for cancer mutations.Several phase III clinical trials testing different cancer vaccine candi-dates are currently ongoing.Exogenous vaccines utilize,for instance,dendritic cell-based and viral vectors-based ap-proaches to boost the immune response in cancer patients.To be successful, these platforms will require applying high-throughput genomics to identify cancer-speci?c mutations and candidate peptide antigens in each patient in order to produce personalized vaccines. An alternative approach,endogenous vaccination,is based on exploiting the local release of antigens that happens upon standard cancer therapy(chemo-therapy or radiotherapy)or oncolytic viral therapy.However,this strategy requires endogenous antigen presentation to be effective,in order to generate therapeutic T cell immunity.Dendritic cells are often skewed by tumors to generate pro-tumor immunity and thus reprogramming of their function in vivo is critical for the success of endogenous vaccination. Increasing the understanding of cancer genomics,the biology of antigen pre-sentation and T cell biology will enable development of next-generation cancer vaccines which,combined with check-point blockade inhibitors,will pave the path to curative therapies for patients with cancer.Personalized

Immunotherapy

Steven A.Rosenberg

National Cancer Institute,NIH

Adoptive cell transfer(ACT)uses patient’s

lymphocytes to treat their autologous

cancer.When tumor in?ltrating lympho-

cytes are used for ACT,they can mediate

complete,likely curative,regression

in patients with metastatic melanoma.

Lymphocytes genetically engineered to

express anti-tumor receptors can treat

patients with refractory lymphomas and

leukemias.However,the majority of

metastatic epithelial cancers are still

resistant to immunotherapy.Recent ap-

proaches using deep exome sequencing

along with high-throughput immunologic

testing opened the door to treat these

common types of cancer and to identify

the rare somatic mutations that are immu-

nogenic.ACT targeting these mutations

is the ultimate‘‘personalized’’cancer

treatment but is contrary to the mantra

of many pharmaceutical companies who

want‘‘drugs in a vial’’that can be mass

produced and distributed.Although this

approach has produced drugs that pro-

long the life of patients with solid meta-

static cancers,curative treatments are

rare and have had limited impact on

overall death rates from cancer.A highly

‘‘personalized’’immunotherapy for com-

mon cancers may require the develop-

ment of a unique drug(autologous lym-

phocytes)for each patient.It will also

need major changes and considerable

?exibility on the part of industry.The

effectiveness of treatment should trump

simplicity of production and convenience

of administration if progress is to be

made in enabling patients with metastatic

cancer to be cured and relish a normal

lifespan.

The New Immune

Engineers

K.Dane Wittrup

Koch Institute for Integrative Cancer Research,MIT

What vaccine best exploits the evolu-

tionary weaknesses of a virus or a tumor’s

mutations?What is the intratumoral

exposure history of intravenously injected

antibodies?How does deregulated

signaling tip the balance from healthy

homeostasis to autoimmune disease?

Can native T cell tropism overcome

physical barriers to macromolecular drug

delivery?How does our antibody reper-

toire respond to therapy or disease?

How might innate and adaptive immuno-

therapies best be combined?How does

lymphatic transport actively regulate

adaptive immunity?Can injectable bio-

materials program an effective anti-tumor

immune response?A common thread

through these varied and timely topics is

the engagement of biological,chemical,

and materials engineers at the forefront.

At their disposal is an analytical toolkit

honed to solve problems in the petro-

chemical and materials industries,which

share the presence of complex reaction

networks and convective and diffusive

molecular transport.Powerful synthetic

capabilities have also been crafted:

binding proteins can be engineered

with effectively arbitrary speci?city and

af?nity,and multifunctional nanoparticles

and gels have been designed to interact

in highly speci?c fashions with cells and

tissues.Fearless pursuit of knowledge

and solutions across disciplinary bound-

aries characterizes this nascent discipline

of immune engineering,synergizing with

immunologists and clinicians to put

immunotherapy into practice.

186Cell161,April9,2015a2015Elsevier Inc.