Hot and
Cold Tumors
Each human
malignancy is uniquely different from every other cancer, but from the point of
view of immunotherapy, there are just two types of tumors: Hot and Cold.
Likewise, there are two types of immunotherapy treatment: Immune response
inducing and anti-immunosuppressive.
There are
at least 100 different types of cancers if they are classified based on their
tissue of origin. Looking more carefully at the cell type from which the malignant
growth originates, there are at least 200 different types of cells in the human
body, each of which can give rise to cancer. Even this is a superficial view
since a cell type will behave differently when it is a different organ. Also, a
tumor can be less or more aggressive, sometimes to the degree where it is
classified as a different cancer. Even if two tumors originate from the same
cell type in the same organ, their mutation profile will be different and thus
in the end every tumor is a unique individual.
Despite all
this complexity, treatments in oncology have traditionally been much less complicated.
“Pancreatic cancer” is treated with drugs X, Y and Z without regard for the
individual characteristics of the tumor, and the same is true for most cancer
types. Perhaps the most glaring example is sarcomas, which lumps more than 50
different tumor types together, but there are only a couple of widely used
therapeutic regimens. In the past two decades treatment paradigms have changed
somewhat for certain tumors such as lung, breast and colon cancer, and melanoma,
where molecular subtypes are treated differently, increasing complexity in
treatment choices.
Immunotherapy
has recently made a breakthrough into treatment of many types of cancers,
including melanoma, lung, kidney, head and neck, urinary tract cancer, lymphoma
and others. Amazingly, what has emerged is that from the point of view of
immunotherapy, there seem to be only two types of tumors: Hot and Cold.
The former
type are characterized by the presence of tumor infiltrating lymphocytes (T-cells,
a type of white blood cell), which are capable of recognizing aberrant proteins
in or on cancer cells. Typically the easiest types of proteins to recognize are
neoantigens (antigen = immunological target), which means proteins not normally
found in the body. Certain types of mutation such as frameshift, point
mutations, in-frame deletions and gene fusions can result in neoantigens. Neoantigens
are more immunogenic (=able to cause an immune response) than overexpression or
misplaced expression of normal antigens. Logically, the more mutations in the tumor,
the more neoantigens, resulting in higher likelihood of T-cells detecting the
tumor.
In theory,
tumor-recognizing T-cells would be expected to kill the cells they detect. This
probably happens all the time in our bodies, and we never knew that we had cancer.
However, eventually some tumors are able to escape detection by the immune
system, in a three-step process known as the three E’s of immunoevasion (Elimination,
Equilibrium, Escape). Every tumor that is diagnosed has been able to escape
killing by T-cells. One key mechanism is development of immunosuppression,
meaning mechanisms that counteract detection and killing by immunological cells.
These immunosuppressed tumors often feature expression of a molecule called
PD-L1. For further reading on this please see my book referenced below.
In contrast
to Hot tumors, Cold tumors don’t have a lot of mutations, often lack
neoantigens and feature low or no T-cells inside the tumors. Since there is
little cellular immunity against the tumor, there is less need for
immunosuppression and therefore PD-L1 expression is typically low. One variant
of a cold tumor is an “immune excluded” tumor where there might be mutations
but because of certain biological reasons the T-cells are unable to penetrate
the tumor.
Fitting
well with classification of tumors into two categories, Hot and Cold, there are
two main types of immunotherapy treatment: 1) immune response inducing and 2)
anti-immunosuppressive therapies.
Examples of
the former category include cancer vaccines, T-cell therapies such as TIL, TCR
and CART therapies, and oncolytic viruses, also known as oncolytic
immunotherapy. Of these approaches, there is one CART approved for leukemia (tisagenlecleucel
or Kymriah) and one oncolytic virus (talimogene laherparepvec or T-Vec or
Imlygic) approved for treatment of melanoma.
It seems likely many more drugs in
these categories will be approved in the next decade. It has not been studied
much but it could be that oncolytic viruses work best in Cold tumors, as
proposed by Taipale and colleagues in 2016. Viruses such as adenovirus are able
to destroy cancer cells in a manner which irritates the immune system, resulting
in a T-cell dominated anti-tumor immune response, which can achieve prominent
therapeutic effects if there was little or no immunosuppression present.
A clearer
breakthrough has already been seen in the latter category. The immunotherapies
most widely used currently (eg nivolumab, pembrolizumab, atezolizumab, avelumab)
block interaction between PD-L1 and its receptor PD-1. These “checkpoint
inhibiting” drugs only work in Hot tumors characterized by neoantigens, T-cells
and PD-L1 expression. They cannot generate new immunity and thus if T-cells
were not present the therapy will probably not work.
Oncologists
love to mix and match ingredients to make their witches’ cocktails. Thus it
comes as no surprise that oncolytic viruses have already been combined with
checkpoint inhibitors, and trials were started even before the difference
between Hot and Cold tumors was understood. These trials are still in their
early phases or in planning but the initial data emerging is awesome. Ribas and
collagues reported that the majority of patients responded emphatically without
severe side effects, and one third had a complete response.
Although
the combination of oncolytic virus with checkpoint inhibition is very well
tolerated, it might represent overtreatment for some patients. It might be
better to study the immunological status of tumors and treat Hot tumors with
checkpoint inhibitors or their combinations, while Cold tumors could be treated
with oncolytic viruses. Impressively, tests allowing distinguishing between Hot
and Cold tumors were rapidly incorporated
into commercially available drug sensitivity kits such as OncoSTRAT&GO and Caris
Molecular Intelligence. Thus, aficionados can already offer this testing to
their patients.
Nevertheless,
since generation of an immune response in the body always results in an
immunosuppressive counter-response (this is how the body protects itself
against auto-immunity), oncolytic viruses might benefit from an
anti-immunosuppressive “companion treatment”. This would prevent dampening and
attenuation of the anti-tumor response.
Tumors have
tremendous capacity for developing resistance, for example through a
target-negative clone. Thus, there might be fewer relapses following checkpoint
inhibition if it would be combined with a therapy such as an oncolytic virus
that can increase the number and broaden the repertoire of tumor detecting
T-cells. The beauty of the oncolytic approach is that it is dynamic and
continuous – whichever epitopes are present in the tumor will be presented to
the immune system.
It is not
trivial at all how these drugs are sequenced and dosed. Also, there are at
least a dozen different types of oncolytic viruses but they are not likely to
be equally effective in generating a T-cell dominated anti-tumor immune
response. Likewise, there are dozens of potentially druggable immune checkpoints.
In summary,
underlying incredible complexity between tumors, in the context of
immunotherapy all tumors seems to fall into one of two classes: Hot or Cold.
With regard to available immunotherapies, oncolytic viruses appear to work in
Cold tumors while checkpoint inhibitors work in Hot tumors. The combination of
these approaches is appealing and could become commonly used in the next decade.
References
Hemminki A.
Crossing the Valley of Death with Advanced Therapy. Published by Nomerta,
Turku, Finland, 2015. Available at http://www.nomerta.net and several e-book
stores globally
Ribas A,
Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ,
Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS,
Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic
Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1
Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi:
10.1016/j.cell.2017.08.027.
Taipale K,
Liikanen I, Koski A, Heiskanen R, Kanerva A, Hemminki O, Oksanen M,
Grönberg-Vähä-Koskela S, Hemminki K, Joensuu T, Hemminki A. Predictive and
Prognostic Clinical Variables in Cancer Patients Treated With Adenoviral
Oncolytic Immunotherapy. Mol Ther. 2016 Aug;24(7):1323-32
