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tumor antigens and are activated. Tumor cells may evade immune responses by losing expression of antigens or major histocompatibility complex (MHC) molecules or by producing immunosuppressive cytokines

or ligands such as PD-L1 for inhibitory receptors on T cells. Tumors may also create an immunosuppressive

microenvironment with regulatory T cells and antiinflammatory myeloid cells. CTL, Cytotoxic T lymphocyte,

MDSC, myeloid derived suppressor cell.

202 CHAPTER 10 Immunology of Tumors and Transplantation

of which would have to be mutated or lost, whereas

mutation in any component of antigen presentation

will lead to failure to present all antigens.

• Tumors engage pathways that inhibit T cell activation. For example, many tumors express PD-L1, a

ligand for the T cell inhibitory receptor programmed

cell death protein 1 (PD-1). Furthermore, tumors,

being persistent, cause repeated stimulation of T

cells specific for tumor antigens. The result is that

the T cells develop an exhausted state, in which they

express high levels of PD-1, cytotoxic T lymphocyte–

associated antigen 4 (CTLA-4), and other inhibitory

molecules, and become unresponsive to antigen.

• Factors in the tumor microenvironment may impair

the ability of dendritic cells to induce strong antitumor immune responses. For example, dendritic cells

that capture tumor antigens often express only low

levels of B7 costimulators, resulting in preferential

engagement of the inhibitory receptor CTLA-4 on

naive T cells in the draining lymph nodes, rather

than the stimulatory receptor CD28 (see Chapter 9).

Some tumors may induce regulatory T cells,

which also suppress antitumor immune responses.

Myeloid-derived suppressor cells, which are developmentally related to neutrophils and monocytes but

have mainly antiinflammatory functions, are abundant in tumors, and are believed to contribute to

immunosuppression.

• Some tumors may secrete immunosuppressive cytokines, such as transforming growth factor ß.

Cancer Immunotherapy

The main strategies for cancer immunotherapy currently

in practice include introduction of antitumor antibodies and autologous T cells that recognize tumor antigens and enhancing patients’ own antitumor immune

responses with antibodies that block immune checkpoints and vaccination. Until recently, most treatment

protocols for disseminated cancers, which cannot be cured

surgically, relied on chemotherapy and irradiation, both of

which damage normal nontumor tissues and are associated with serious toxicities. Because the immune response

is highly specific, it has long been hoped that tumorspecific immunity may be used to selectively eradicate

tumors without injuring the patient. Only recently has

the promise of cancer immunotherapy been realized in

patients. The history of cancer immunotherapy illustrates

how the initial, often empirical, approaches have been

largely supplanted by rational strategies based on our

improved understanding of immune responses (Fig. 10.5).

Passive Immunotherapy With Monoclonal

Antibodies

A strategy for tumor immunotherapy which has been in

practice for a limited number of tumors for decades relies

on the injection of monoclonal antibodies which target cancer cells for immune destruction or inhibition of

growth (Fig. 10.6A). Monoclonal antibodies against various tumor antigens have been used in many cancers. The

antibodies bind to antigens on the surface of the tumors

(not the neoantigens produced inside cells) and activate

(1991, 1994) Discovery of

FDA approval of Anti-CTLA4

(ipilumimab) for melanoma

1863 1898 1957 1976 1983 1985 1991 2002 2009 2010 2011 2014

Fig. 10.5 History of cancer immunotherapy. Some of the important discoveries in the field of cancer immunotherapy are summarized. BCG, Bacillus Calmette-Guerin; CAR, chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; FDA, Federal Drug Administration; HPV, human

papillomavirus; IL-2, interleukin-2; PD-1, programmed cell death protein 1. (Modified from Lesterhuis WJ,

Haanen JB, Punt CJ: Cancer immunotherapy—revisited, Nature Reviews Drug Discovery 10:591–600, 2011.)

CHAPTER 10 Immunology of Tumors and Transplantation 203

host effector mechanisms, such as phagocytes, NK cells,

or the complement system, that destroy the tumor cells.

For example, an antibody specific for CD20, which is

expressed on B cells, is used to treat B cell tumors, usually

in combination with chemotherapy. Although normal

B cells are also depleted, their function can be replaced

by administration of pooled immunoglobulin from normal donors. Because CD20 is not expressed by hematopoietic stem cells, normal B cells are replenished after

the antibody treatment is stopped. Other monoclonal

antibodies that are used in cancer therapy may work by

blocking growth factor signaling (e.g., anti-Her2/Neu for

breast cancer and anti–EGF-receptor antibody for various tumors) or by inhibiting angiogenesis (e.g., antibody

against the vascular endothelial growth factor for colon

cancer and other tumors).

Adoptive T Cell Therapy

Tumor immunologists have attempted to enhance antitumor immunity by removing T cells from cancer patients,

activating the cells ex vivo so there are more of them

and they are more potent effector cells, and transferring

the cells back into the patient. Many variations of this

approach, called adoptive T cell therapy, have been tried.

• Adoptive therapy with autologous tumor-specific

T cells. T cells specific for tumor antigens can be

detected in the circulation and among tumorinfiltrating lymphocytes of cancer patients. T cells

can be isolated from the blood or tumor biopsies of a

patient, expanded by culture with growth factors, and

injected back into the same patient (see Fig. 10-6A).

Presumably, this expanded T cell population contains

activated tumor-specific CTLs, which migrate into the

tumor and destroy it. This approach, which has been

combined with administration of T cell-stimulating

cytokines such as interleukin-2 (IL-2) and traditional

chemotherapy, has shown inconsistent results among

different patients and tumors. One likely reason is that

the frequency of tumor-specific T cells is too low to be

effective in these lymphocyte populations.

• Chimeric antigen receptor (CAR) expressing T cells.

In a more recent modification of adoptive T cell

Passive immunity by transfer of autologous T cells or monoclonal antibodies

Adoptive T cell therapy with CAR-T cells

expanded in vitro Transfer into

anti-CD3 and anti-CD28,

transduce with CAR

gene encoding tumorspecific antigen receptor

Tumor cell

Fig. 10.6 Tumor immunotherapy by adoptive transfer of antibodies and T cells. A, Passive immunotherapy with tumor specific T cells or monoclonal antibodies. B, Adoptive T cell therapy with CAR-T cells:

T cells isolated from the blood of a patient are expanded by culture with anti-CD3 and anti-CD28, genetically

modified to express recombinant chimeric antigen receptors (CARs) (see Fig. 10-7), and transferred back into

the patient.

204 CHAPTER 10 Immunology of Tumors and Transplantation

Fig. 10.7 Chimeric antigen receptor. The receptor that is

expressed in T cells consists of an extracellular Ig part that

recognizes a surface antigen on tumor cells and intracellular

signaling domains from the TCR complex and costimulatory

receptors that provide the signals that activate the killing function of the T cells.

therapy, blood T cells from cancer patients are transduced with viral vectors that express a chimeric

antigen receptor (CAR), which recognizes a tumor

antigen and provides potent signals to activate the T

cells (see Fig. 10-6B). The CARs currently in use have

a single chain antibody-like extracellular portion with

both heavy- and light-chain variable domains, which

together form the binding site for a tumor antigen

(Fig. 10-7). The specificity of the endogenous T cell

receptors (TCRs) of the transduced T cells is irrelevant to the effectiveness of this approach. The use of

this antibody-based antigen recognition structure

avoids the limitations of MHC restriction of TCRs

and permits the use of the same CAR in many different patients, regardless of the human leukocyte antigen (HLA) alleles they express. Furthermore, tumors

cannot evade CAR-T cells by downregulating MHC

expression. In order to work in T cells, the CARs have

intracellular signaling domains of both TCR complex

proteins, for example the ITAMs of the TCR complex

? protein, and the signaling domains of costimulatory

receptors such as CD28 and CD137. Therefore, upon

antigen binding, these receptors provide both antigen

recognition (via the extracellular immunoglobulin

[Ig] domain) and activating signals (via the introduced cytoplasmic domains). CAR-expressing T cells

are expanded ex vivo and transferred back into the

patient, where they recognize the antigen on the tumor

cells and become activated to kill the cells. CAR-T

cell therapy targeting the B cell protein CD19, and

more recently CD20, has shown remarkable efficacy

in treating and even curing B cell-derived leukemias

and lymphomas that are refractory to other therapies.

CARs with other specificities for different tumors are

in development and clinical trials. The most serious

toxicity associated with CAR-T cell therapy is a cytokine release syndrome, mediated by massive amounts

of inflammatory cytokines, including IL-6, interferon-?, and others, that are released because all of the

injected T cells recognize and are activated by the

patients’ tumor cells. These cytokines cause high fever,

hypotension, tissue edema, neurologic derangements,

and multi-organ failure. The severity of the syndrome

can be mitigated by treatment with anticytokine antibodies. CAR-T cell therapy may also be complicated

by on-target, off-tumor toxicities, if the CAR-T cells

are specific for an antigen present on normal cells as

well as tumors. In the case of CD19- or CD20-specific

CARs, the therapy results in depletion of normal B

cells, requiring antibody replacement therapy to prevent immunodeficiency. Such replacement may not be

feasible for other tissues that are destroyed because of

the reactivity of the CAR. Although CAR-T cell therapy is effective against leukemias and tumors in the

blood (to which the injected T cells have ready access),

it has so far not been successful in solid tumors because

of difficulties in getting T cells into the tumor sites and

the challenge of selecting optimal tumor antigens to

target without injuring normal tissues.

Immune Checkpoint Blockade

Blocking inhibitory receptors on T cells or their ligands

stimulates antitumor immune responses. The realization that tumors evade immune attack by engaging regulatory mechanisms that suppress immune responses has

led to a novel and remarkably effective new strategy for

CHAPTER 10 Immunology of Tumors and Transplantation 205

tumor immunotherapy. The principle of this strategy is to

boost host immune responses against tumors by blocking

normal inhibitory signals for T cells, thus removing the

brakes (checkpoints) on the immune response (Fig. 10.8).

This has been accomplished with blocking monoclonal

antibodies specific for the T cell inhibitory molecules

CTLA-4 and PD-1, first approved for treating metastatic

melanoma in 2011 and 2014, respectively. Since then, the

use of anti-PD-1 or anti-PD-L1 antibodies has expanded

to many different cancer types. The most remarkable

feature of these therapies is that they have dramatically improved the chances of survival of patients with

advanced, widely metastatic tumors, which previously

were almost 100% lethal within months to a few years.

The efficacy of antibodies specific for other T cell inhibitory molecules, such as LAG-3 and TIM-3, are being

tested in clinical trials. There are several novel features

of immune checkpoint blockade and limitations that still

need to be overcome to enhance their usefulness.

• Although the efficacy of checkpoint blockade therapies

for many advanced tumors is superior to any previous

form of therapy, only a subset of patients (25% to 40%

at most) respond to this treatment. The reasons for this

poor response are not well understood. Nonresponding tumors may induce T cell expression of checkpoint

molecules other than the ones being targeted therapeutically, or they may rely on evasion mechanisms other

than engaging these inhibitory receptors. Oncologists

Primed CTL capable

of killing tumor cells

CTL-mediated killing of tumor cells

Induction of anti-tumor immune response in lymph node

No costimulation Costimulation

T cell inhibition No T cell inhibition

Fig. 10.8 Tumor immunotherapy by immune checkpoint blockade. Tumor patients often mount ineffective T cell responses to

their tumors because of the upregulation of inhibitory receptors such as CTLA-4 and PD-1 on the tumor specific T cells, and expression

of the ligand PD-L1 on the tumor cells. Blocking anti-CTLA4 antibodies (A) or anti-PD-1 or anti-PD-L1 antibodies (B) are highly effective

in treating several types of advanced tumors by releasing the inhibition of tumor-specific T cells by these molecules. Anti-CTLA-4 may

work by blocking CTLA-4 on responding T cells (shown) or on Treg. CTL, Cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; TCR, T cell receptors.

206 CHAPTER 10 Immunology of Tumors and Transplantation

and immunologists are currently investigating which

biomarkers will predict responsiveness to different

checkpoint blockade approaches.

• One of the most reliable indictors that a tumor will

respond to checkpoint blockade therapy is if it carries a high number of mutations, which correlates

with high numbers of neoantigens and host T cells

that can respond to those antigens. In fact, tumors

that have deficiencies in mismatch repair enzymes,

which normally correct errors in DNA replication

that lead to point mutations, have the highest mutation burdens of all cancers, and these cancers are the

most likely to respond to checkpoint blockade therapy. Remarkably, anti-PD-1 therapy is now approved

for any recurrent or metastatic tumor with mismatch

repair deficiencies, regardless of the cell of origin or

histologic type of tumor. This is a paradigm shift in

how cancer treatments are chosen.

• The combined use of different checkpoint inhibitors,

or one inhibitor with other modes of therapy, will

likely be necessary to achieve higher rates of therapeutic success. The first approved example of this is

the combined use of anti-CTLA-4 and anti-PD-1 to

treat melanomas, which was shown to be more effective than anti-CTL-4 alone. This reflects the fact that

the mechanisms by which CTLA-4 and PD-1 inhibit

T cell activation are different (see Fig. 10.8). There

are numerous ongoing or planned clinical trials using

combinations of checkpoint blockade together with

other strategies, such as small molecule kinase inhibitors, oncolytic viral infection of tumors, and other

immune stimulants.

• The most common toxicities associated with checkpoint blockade are autoimmune damage to organs.

This is predictable, because the physiologic function

of the inhibitory receptors targeted is to maintain tolerance to self antigens (see Chapter 9). A wide range

of organs may be affected, including colon, lungs,

endocrine organs, heart, and skin, each requiring

different clinical interventions, sometimes including

cessation of the life-saving tumor immunotherapy.

Stimulation of Host Antitumor Immune Responses

by Vaccination With Tumor Antigens

One way of stimulating active immunity against tumors

is to vaccinate patients with their own tumor cells or

with antigens from these cells. Unlike standard antimicrobial vaccines, which are prophylactic in that they

prevent infections, tumor vaccines are meant to be

therapeutic, in that they stimulate immune responses to

attack cancers that have already developed. An important reason for defining tumor antigens is to produce and

use these antigens to vaccinate individuals against their

own tumors. Most tumor vaccines tried to date have

used antigens that are shared by the same type of cancers

in different patients. These antigens are usually differentiation antigens that identify cells of a particular lineage,

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