Immunity to Cancers

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Chapter 22 Immunity to Cancers

Summary

• The immune system can potentially survey the body for some types of developing tumor.

• Tumors can induce immunity. Mice, rats, hamsters, and frogs can be immunized against tumors. In most tumors of animals, tumor immunity elicited by immunization is specific (or strongest) to the individual tumor that was used to immunize.

• Tumor antigens have been characterized by three means – immunization-challenge experiments, T cell reactivity, and antibody reactivity. Immunization-challenge experiments have uncovered the immunogenicity of heat-shock protein-chaperoned antigenic peptides. Antigens identified by reactivity to T cells and antibodies include individual tumor-specific mutated antigens, cancer testes antigens, differentiation antigens, and viral tumor antigens.

• Vigorous anti-tumor immune responses are compromised by regulatory mechanisms. Tumors elicit immunity in their primary host, and such immunity is downregulated. Regulatory cells such as CD25⁺ CD4⁺ T cells and inhibition of activated anti-tumor T cells through T cell molecules such as CTLA-4 are involved in downregulation of tumor immunity.

Immune surveillance and protection from cancer

Cancer appears to have engaged the minds of immunologists almost since the beginning of immunology itself. Ehrlich, who opined on all things immunological, believed that the immune system could protect the host from cancer.

Burnet and Thomas refined that idea into the immune surveillance hypothesis of cancer. The hypothesis lived in limbo for several decades, failing to thrive and failing to die, until very recently when the work of Old, Schreiber, and their colleagues demonstrated that mice with a compromised immune status were more prone than immunocompetent mice to develop an array of cancers.

The immune surveillance hypothesis is often regarded as the intellectual underpinning of cancer immunology. Although the hypothesis itself has contributed little to our attempts to treat cancer through immunological means, it has profound implications for understanding the functions of the immune system.

Does infection have an anti-cancer effect?

German physicians in the 19th century noted dramatic regressions of cancer in occasional patients who developed streptococcal infections. These anecdotes led to a systematic exploration of infections/fever as an immunotherapeutic modality by William Coley, a New York City surgeon.

The work of Coley and his predecessors, suggesting that non-specific stimulation of the immune system, such as by an infection, can have an anti-cancer effect, remains a key idea in cancer immunology. It is only a small exaggeration to say that every idea in cancer immunity has been interpreted at some time or another, in terms of Coley’s observations.

Tumor immunity in the primary host

In hindsight, these successful immunizations were simply a result of allogeneic differences between tumors and the host strain of mouse, a theme that played a seminal role in definition of the MHC, but had no relevance for cancer immunity.

Q. What will happen when a tumor from a mouse of one MHC haplotype is transplanted into a recipient with a different haplotype on the first occasion or the second?

A. A transplantation rejection reaction will ensue, and these reactions display specificity and memory (see Chapter 21).

Nonetheless, amidst the barrage of experiments where MHC-mismatched tumors were transplanted into mice, were the experiments of Ludwik Gross, and later those of Prehn and Main, and of George and Eva Klein, who showed that, even when MHC-matched tumors were used to immunize mice, protection against subsequent tumor growth could be achieved (Fig. 22.1). These studies led to two principles, which have informed much of cancer immunology since and are discussed below.

Fig. 22.1 Immunogenicity of chemically induced tumors

(1) Mice immunized with tumor cells are protected against subsequent tumor growth. (2) The primary animal that develops the tumor is also immune to subsequent challenges with the same tumor.

Cancers elicit protective immunity in the primary and syngeneic host

Mice and rats of a given haplotype can be immunized with irradiated cancer cells that arose in animals of the same haplotype. When they are challenged with live cancer cells, they are able to resist the tumor challenge. The following further observations and deductions have been derived from these results.

• The immunogenicity of tumors has provided the foundation stone for the idea of tumor-specific antigens. If one could immunize, then antigens must exist.

• Tumor immunity depends on many factors. The degree of tumor immunity depends upon the type of cancer and the method of its induction, or lack of induction. UV-induced cancers are highly immunogenic, methyl-cholanthrene-induced tumors less so, and spontaneous tumors even less so. Nonetheless, immunogenicity of tumors has been demonstrated in all model systems tested.

• The primary animal develops immunity to subsequent tumor challenge. Furthermore it is also immune to subsequent challenges with the same tumor (see Fig. 22.1).

• Protective immunity is only seen in prophylactic immunization and not therapeutic immunization – once a mouse has been implanted with a tumor, immunization with irradiated cancer cells (derived from the growing tumor) does nothing to mitigate tumor growth (Fig. 22.2). Exploration of differences between prophylaxis and therapy has led to fundamental insights into tumor immunity.

Fig. 22.2 Difference between prophylaxis against future tumors and therapy of pre-existing tumors

Protective immunity is only seen in prophylactic immunization and not therapeutic immunization – once a mouse has been implanted with a tumor, immunization with irradiated cancer cells (derived from the growing tumor) does nothing to mitigate tumor growth.

It is obviously not possible to test immunogenicity of tumors in humans by the transplantation-challenge experimental paradigm. There is no other reliable method of determining immunogenicity of tumors. It is therefore impossible to comment on the immunogenicity of human tumors. Much of the work in human cancer immunity has been done with melanomas leading to suggestions that, among human tumors, melanomas are particularly immunogenic. This is an erroneous belief – melanomas are simply the easiest human tumors to culture in vitro and hence the easiest to study.

Specific immunity may develop to induced and spontaneous tumors

When mice are immunized against a given fibrosarcoma, they are rendered immune to that fibrosarcoma, but only to that individual fibrosarcoma or lines derived from it. If the mice are challenged with another fibrosarcoma, even one induced by the same carcinogen, tumor growth is unaffected by the prior immunization.

The most extensive interrogation of the individually distinct antigenicity of chemically induced tumors was carried out by Basombrio and Prehn. They induced fibrosarcomas in 25 syngeneic BALB/c mice using methyl-cholanthrene and tested the immunogenicity of each one against all other tumors in an immunization-challenge model. They concluded that, even though all tumors were induced at the same time, in the same strain of mice of the same age by the same carcinogen and were histologically all fibrosarcomas, they were antigenically individually distinct. Independent tumors induced by the same carcinogen in the same mouse are also antigenically distinct.

Q. What can you infer about the nature of the immune response to tumors from this observation?

A. It must involve the adaptive immune system.

Spontaneous tumors are also antigenically distinct

Cross-reactivity among tumors does occur occasionally. Typically, such cross-reactive immunity has been observed to be significantly weaker than the individually specific antigenicity. Efforts at characterization of such cross-reactive tumor-protective antigens have not made much headway, except in the case of virally induced tumors. In contrast, there has been considerable success in identification of individually distinct antigens.

In addition to these experimental studies, several clinical observations point to the existence of tumor-protective immunity in humans. These include the increased relative risk of cancers in patients who are immunosuppressed because they are kidney transplant recipients (Fig. 22.3) or for a variety of other reasons (Fig. 22.4).

Fig. 22.3 Relative risk of tumors in immunosuppressed kidney transplant

In all forms of immunodeficiency the relative risk of developing tumors in which viruses are known to play a role is greatly increased. This is the case for all those listed except cancer of the lung. The relative risks vary in different studies according to the duration of follow-up and the presence of co-factors such as sunlight for skin cancer.

Fig. 22.4 Tumor viruses and immunodeficiency

Skin cancer is the most common form of tumor in absolute numbers in organ transplant recipients. In other forms of immunodeficiency, tumors of the immune system dominate. Most normal adults carry both Epstein–Barr virus (EBV) and many papilloma viruses throughout life with no ill effects because they have antiviral immunity.

Q. The observation that immunosuppressed individuals are more susceptible to tumors can be explained in at least two different ways. Suggest what these explanations might be

A. The individual may be unable to control virus infections that lead to cancer (oncogenic viruses), or they may be unable to survey and control primary tumors that arise by mutation. The explanations are not mutually exclusive.

Characterization of tumor antigens

The two broad approaches to the identification of tumor antigens are shown in Figure 22.5 and discussed individually below. Not surprisingly, the approaches have yielded results that are not fully concordant. These differences have helped highlight a fascinating interplay between immunity and tolerance to tumors, discussed below.

Fig. 22.5 Comprehensive list of major types of tumor antigen

A comprehensive list of the major types of tumor antigen.

Tumor-specific antigens defined by immunization all belong to the family of HSPs

When tumors were biochemically fractionated and individual protein fractions tested for their ability to elicit protective tumor immunity, a number of tumor-protective antigens were identified in diverse tumor models, such as mouse sarcomas, melanomas, colon and lung carcinomas, and rat hepatomas.

Interestingly, regardless of the tumor models used, all antigens were found to belong to the family of proteins known as the heat-shock proteins (HSPs), which:

• could elicit protective immunity;

• were of the HSP90 (gp96 and HSP90), HSP70 (HSP110 and HSP/c70), calreticulin, and HSP170 (also known as grp170) families.

‘Tumor-specific antigens’ recognized by T cells show a wide spectrum of specificity

Many studies have identified tumor-reactive T cells in blood or within a tumor, and these findings have thus supported the idea of tumor antigens.

The work of Thierry Boon and his colleagues first made it technically possible to identify the CTL epitopes of cancer cells being recognized by the tumor-reactive T cells.

Although the idea of tumor-specific antigens in mouse models of cancer was based on tumor rejection in vivo and thus had connotations of tumor specificity, the tumor antigens defined by tumor-reactive T cells show a wider spectrum of specificity, and their connection with tumor immunity in vivo is tenuous.

The T cell-defined tumor antigens of murine tumors have been defined in a mastocytoma, two fibrosarcomas, a squamous cell carcinoma, and a colon carcinoma because these tumor lines are in popular use. Similarly, much of the corresponding work in human tumors has been carried out in melanomas because melanoma cell lines are easier to establish in culture, rather than because of any unique immunogenicity of human melanomas.

The tumor antigens identified as T cell epitopes fall into the following categories (see Fig. 22.5).

Cancer/testes antigens are expressed only in testes

Cancer/testes (CT) antigens, as the name suggests, are expressed on cancer cells and in testes, but not in other normal adult tissues. MAGE, BAGE, GAGE, and NY-ESO1 are examples of this class of antigen. Individual epitopes within CT antigens have been defined for CD8 as well as CD4 lymphocytes. Clinical trials with the MAGE antigen are currently underway.

Differentiation antigens are lineage specific and not tumor specific

Differentiation antigens, which are lineage specific, but not tumor specific, are expressed on normal tissues (melanocytes) as well as tumors (melanomas). Examples of such antigens include MART-1/Melan-A, tyrosinase, gp100, Trp1, and Trp2. Individual epitopes within differentiation antigens have been defined for CD8 as well as CD4 lymphocytes. Most differentiation antigens have been identified in human melanomas but in randomized clinical trials, there is little evidence that immunization with them confers clinical benefit to cancer patients.

Unique tumor-specific antigens have been characterized in melanomas

Individually tumor-specific or unique antigens presented by MHC class I or class II molecules have been characterized in human melanomas (see Fig. 22.5).

In terms of their specificity, these antigens are most similar to the individually tumor-specific antigens of murine tumors defined by tumor transplantation studies. Immunization with these antigens renders the mice resistant to tumor challenge. They are the only tumor antigens that have been shown to possess this essential property. The defined unique antigens of human tumors have not been tested for clinical activity.

T cell epitopes of viral antigens have been identified

T cell epitopes of viral antigens of virus-induced tumors have been identified such as:

• the T antigen of SV40 and the polyoma viruses;

• the E6 and E7 antigens of the human papilloma viruses that cause cervical cancer; and

• a number of antigens of EBV (Fig. 22.8).

Fig. 22.8 Microorganisms and human tumors

EBV causes Burkitt’s lymphoma in endemic malaria areas of Africa and nasopharyngeal carcinoma in China, suggesting that co-factors, either genetic or environmental, are required for tumor development. Helicobacter pylori is the only bacterium so far known to be involved in the etiology of human cancer.

Some of these, such as the HPV antigens, are used for prophylactic vaccination (see Chapter 18) and are being tested for clinical activity in human tumors.

‘Tumor-specific antigens’ defined by antibodies are rarely tumor specific

The search for antibodies that discriminate between cancer cells and normal cells has a long pedigree and has been carried out with the whole range of tools starting from antisera to panning antibody libraries. This search has been largely unsuccessful and rarely have tumor-specific antibodies been generated. Most anti-tumor antibodies, like anti-tumor T cells, happen to recognize CT antigens, differentiation antigens, and even more broadly distributed common antigens (see Fig. 22.5).

Antibodies to a B cell surface antigen, CD20, epidermal growth factor receptor, and HER2/Neu have now been approved for treatments, respectively, of B lymphoma, colorectal cancers, and breast cancers. Although these antibodies have shown some efficacy in the treatment of certain cancers at certain stages, they:

• do not recognize tumor-specific antigens;

• are actually used as pharmacological rather than immunological reagents.

Antibodies used in the diagnosis of cancer may not be tumor specific

As serum antibodies are technically easy to measure, they have always attracted the attention of diagnosticians (Fig. 22.w2 ). Thus, antibody to carcinoembryonic antigen (CEA) is often used as a marker for progression or status of certain carcinomas; however, CEA or other such antigens are not tumor-specific antigens and diagnostic markers need not necessarily have the specificity required of a ‘tumor-specific antigen’.

Fig. 22.w2 Markers for detection of cancers and antibodies used for therapy of selected cancers

Neither the ‘antigens’ used as diagnostic cancer markers (1) nor the antibodies used for therapy of selected cancers (2) are tumor specific. (AML, acute myeloid leukemia; CLL, chronic lymphatic leukemia).

Mutated oncogenes could be a source of tumor specific antigens

The discussion thus far has dealt with tumor antigens defined by experimental tools. Several additional antigens have been tested as tumor antigens because of their restricted or relatively restricted expression on cancer cells, with the reasonable assumption that they would elicit tumor-specific and perhaps tumor-protective immune responses. Antigenic epitopes generated by mutated oncogenes such as ras and p53 as well as gene fusion-generated oncogenes such as bcr-abl, which are, by definition, tumor specific, come into this category. These antigens could, in principle, be broadly applicable tumor antigens, particularly in those instances where specific mutations are seen in different individuals.

The idea that mutant proteins are recognized by the immune system has been explored to a degree in murine and human systems, and immune reactivity to peptides derived from such mutated oncogenes has been detected. However, no evidence of their general tumor-protective immunogenicity has emerged.

It is conceivable that the immune response to these alterations is tolerized early in tumorigenesis and, indeed, such tolerization may be a pre-condition for tumorigenesis.

Anti-tumor immune responses

Successful tumor immunity is rare in patients who have cancer

Mechanisms of tumor immunity have been examined mostly in mouse models, partly because successful tumor immunity is rare in patients who have cancer. Moreover, as successful tumor immunity is rare in the tumor-bearing setting in mouse models, much of the work has been done in a prophylactic setting, which is not applicable to the human situation.

Not surprisingly, the pathways to elicitation of immune response to tumors are straightforward (Fig. 22.9). The tumor inoculum (with its antigenic load) is taken up by the APCs at the site of immunization and is cross-presented by them to the naive CD8 cells in the draining lymph nodes. Both responses are generally necessary in the mouse models tested and both responses have been shown to be present in the cancer patients studied.

Fig. 22.9 A working diagram of the possible mechanism of tumor immunity

The tumor inoculum (with its antigenic load) is taken up by APCs at the site of immunization and is cross-presented by them to the naive CD8 cells in the draining lymph nodes.

Antibodies have not generally been shown to be protective in the natural setting.

NK cell activity has been demonstrated most commonly, but its necessity has rarely been examined critically. In the few studies where it has been examined, it appears that NK cells play a crucial role in the immune response to cancers. Clearly, the cytokines necessary for the effector functions of CD4, CD8, and NK cells, such as IL-2, IFNγ, IL-12, and others, are necessary as well.

Despite an immune response, tumors continue to grow

Despite clear evidence for the existence of tumor-specific antigens and the immune response elicited by them, tumors generally continue to grow. In this regard, Ehrlich made a curious observation that remains at the center of cancer immunity. He noted that animals with already growing tumors were strangely resistant to a second tumor challenge even as the first tumor kept growing (Fig. 22.10). This phenomenon, termed concomitant immunity as early as 1908, remained relatively unexamined until recently.

Fig. 22.10 Concomitant immunity

Animals with already growing tumors are resistant to a second tumor challenge even as the first tumor continues to grow.

Concomitant immunity shows two aspects of tumor immunity

Concomitant immunity shows two aspects of tumor immunity:

• first, a growing tumor elicits in the primary host a tumor-protective immune response;

• second, although this response is sufficient to eliminate a nascent tumor, it fails to eliminate the tumor that elicited the response.

It was shown that concomitant immunity was tumor specific and operational only within a narrow window of 7–10 days after tumor implantation; if the second tumor was implanted beyond this time, it was not rejected. The lack of immunity beyond the narrow window was attributable to a new population of suppressor T cells that appeared at that time (Fig. 22.11). Similar to the phenomenon of concomitant immunity, it was also noted that mice in the process of rejecting an allograft were unable to concomitantly reject a growing tumor bearing the same alloantigens as the allograft.

Fig. 22.11 Effector CD8 and suppressor CD4 cells in concomitant immunity

Concomitant immunity is tumor specific and operational only within a narrow window of 7–10 days after tumor implantation. If the second tumor is implanted beyond this time, it is not rejected. The lack of immunity beyond the narrow window is attributable to a new population of suppressor T cells that appear at that time.

Q. How do you interpret the observation above?

A. One would expect an allograft to be rejected in these circumstances, therefore there is something about the tumor that allows it to evade a normal allospecific rejection reaction.

Immunization is effective prophylactically but rarely as therapy

The findings discussed above fit in well with the observations that, although naive mice can be immunized successfully using irradiated tumor cell vaccines in almost any tumor model, the same irradiated cell vaccine is ineffective at treating established tumors.

Prophylaxis is relatively effective, even if begun as late as 3 days before tumor implantation, but therapy is ineffective even if begun as early as 2 days after tumor implantation (see Fig. 22.2).

It is easy, and incorrect, to infer from these observations that the tumor-bearing mice or cancer patients are generally immunosuppressed. Tumor-bearing mice generally mount a vigorous immune response to model antigens and even unrelated tumors, almost until the very end of their lives. Similarly, patients with cancer do not generally succumb to the opportunistic infections that are the hallmark of general immunosuppression.

The naive state and tumor-bearing state are essentially different

Collectively, the observations above have shaped the thinking that, immunologically the tumor-bearing host is in a radically different state compared with the naive host.

What are the mechanisms behind this change of status? They are exactly the same as envisaged for the mechanisms for the initiation and maintenance of peripheral tolerance. None of the explanations is fully satisfactory by itself, but each perhaps contributes to the final state of tolerance in some measure. Immune unresponsiveness per se is addressed in detail in Chapter 19. Aspects that are of specific relevance to tumor immunity include:

• inhibitory cytokines including TGFβ and IL-10;

• inhibition of T cell activity through CTLA-4 and PD1;

• down-regulation of the immune response through regulatory T cells;

• resistance to recognition by down-regulation of MHC class I molecules; and

• generation of antigen-loss variants.

Downregulation of MHC I molecule expression may result in resistance to recognition and lysis

A number of studies have shown:

• downregulation of expression of one or more MHC class I alleles;

• loss of β₂-microglobulin; or

• loss or downregulation of any of the several components of the antigen processing machinery.

Although these alterations are clearly likely to inhibit recognition of tumor cells by T cells, they are also more likely to make tumors more susceptible to NK cells.

On the whole, it is not clear what effect, if any, these alterations have on the net ability of a tumor to escape the immune response in vivo.

Generation of antigen-loss variants is another mechanism that no doubt plays a role to some degree in the immunological escape of tumor cells. However, because we do not yet have a significant knowledge of the identity of truly tumor-protective antigens, the role of antigen-loss variants cannot be critically examined.

T cell activity is inhibited through CTLA-4

An exciting explanation for unresponsiveness is the role of inhibition of T cell activity through CTLA-4.

Q. What are the functions of CD28 and CTLA-4 (CD152) on T cells?

A. CD28 transduces co-stimulatory signals to the T cell, while CTLA-4 also ligates B7, but is inhibitory (see Fig. 22.12).

CTLA-4 inhibits the T cell by raising the stimulatory threshold or by inhibiting the proliferative drive of T cells (Fig. 22.12). The biological role of CTLA-4 appears to lie in limiting the T cell response to foreign antigens as well as to autoantigens.

Fig. 22.12 Mechanism of action of anti-CTLA-4 antibody

CTLA-4 inhibits the T cell by raising the stimulatory threshold or by inhibiting the proliferative drive of T cells.

Administering antibodies to CTLA-4 (that inhibit CTLA-4:B7 interactions) to mice bearing a broad array of tumors inhibited tumor growth, even when the antibody was administered after the tumors were visible and palpable (Fig. 22.w3 ). Such activity was generally seen only against the more immunogenic tumors and not against a poorly immunogenic melanoma (e.g. B16). In that instance, combination of anti-CTLA-4 antibody with a vaccine consisting of irradiated melanoma cells that were also transfected with the cytokine granulocyte–macrophage colony stimulating factor (GM-CSF), resulted in a stronger anti-tumor response than by anti-CTLA-4 antibody or the vaccine alone. Clinical development of this idea is discussed below.

Fig. 22.w3 Mouse tumor rejection using anti-CTLA-4 antibody

Administering anti-CTLA-4 to mice bearing a broad array of tumors inhibited tumor growth. Such activity was generally seen only against the more immunogenic tumors and not against poorly immunogenic tumors. The arrows denote the administration of antibodies.

Abrogation of CD25⁺ cells leads to protective tumor immunity

The notion that progressive tumor growth results in the generation of inhibitory influences on the anti-tumor immune response is further supported by the recent work on the CD25⁺ CD4⁺ Treg cells (see Chapter 11). These cells have been shown to suppress CD8⁺ T cell responses in general, including autoimmune responses.

Recent studies have shown that abrogation of the CD25⁺ subpopulation (through anti-CD25 antibodies or through genetic manipulation) in tumor-bearing mice leads to a robust T cell response and protective tumor immunity even in an aggressive tumor model such as the B16 melanoma. Conversely, re-addition of these cells can suppress the anti-tumor immune response.

Results consistent with these have been observed in patients with melanoma whose regulatory CD4⁺ T cells specifically inhibit the CD8⁺ activity against autologous melanoma cells, but not against other targets.

More recent studies have examined this paradigm through the prism of the CD25⁺ T cells. In a study of patients with ovarian cancer, such cells were shown to be associated with a higher risk of death and reduced survival. Interestingly, the CD25⁺ T cells were shown to migrate preferentially to the solid tumors and the ascites, but rarely to the draining lymph nodes.

Such results indicate that, despite the poor clinical outcomes in advanced cancer, the host does mount a vigorous anti-tumor immune response, which is compromised by regulatory mechanisms. Manipulation of such regulatory mechanisms for enhancing cancer immunity is bound to influence the fine balance between tolerance and autoimmunity. In certain contexts, that may be a reasonable price to pay.

Immunotherapy for human cancer

Animal models are limited in the translation of therapy

There exists a ‘common wisdom’ but incorrect belief, that treatment of cancers of mice is easy and has no bearing on treatment of human cancers. Mouse tumors are hard to cure – not a single publication reports curing a mouse with stage IV disseminated disease.

Most approaches study prophylactic vaccination in mice, a smaller number begin treatment on the day of tumor challenge, and only a handful of studies begin treatment more than 10 days after tumor challenge. In most mouse tumor models, mice die within 4–6 weeks of tumor challenge, and thus the window of treatment is extremely narrow.

Most approaches to immunotherapy of human cancer have either never been tested in appropriate mouse models or have failed to show anti-tumor activity when tested. It is important to bear this in mind while examining the three major categories of approaches to immunotherapy of human cancer, discussed below.

Antibodies have been used successfully

As antibodies are the oldest known immunological reagents, it is only to be expected that the first, and thus far among the most successful, approaches to human cancer immunotherapy has been made using these reagents.

Nearly 20 years ago, Ronald Levy and colleagues treated patients with B cell lymphomas using individual patient’s tumor-specific anti-idiotypic antibodies on the premise that the antibodies will recognize and help eliminate their targets – the surface immunoglobulin on the monoclonal lymphomas. The treatment was successful clinically, leading to significant objective tumor regressions, but was limited by the re-emergence of escape variants that did not express the idiotype. This approach has not been pursued further, but remains a powerful reminder of what true tumor-specific antibodies can do to real-life tumors.

Selected antibodies are now approved for clinical use, but these represent pharmacological rather than immunological use of antibodies and include antibodies to:

• CD20 – rituximab – against B cell lymphoma;

• HER2/Neu – trastuzumab (Herceptin®) – against breast cancer;

• epidermal growth factor receptor – cetuximab (Erbitux®) – against colon cancer.

It is ironic that the anti-tumor antibodies that may recognize truly or relatively tumor-specific molecules, and that were the earliest hopes of much of the efforts in this area, have yet to enter the phase of randomized clinical testing. Such antibodies are difficult to characterize and therefore have been slow in development.

Vaccination can be used to treat cancer

Although the term vaccination is typically used to indicate prophylactic vaccination, cancer researchers use it to indicate the treatment of someone who already has cancer, with agents that stimulate anti-cancer immune response. Several vaccination approaches are currently being pursued (Fig. 22.13).

Fig. 22.13 Vaccination approaches to immunotherapy of human cancer currently being tested

Several vaccination approaches are currently being pursued.

The idiotypes of B lymphomas have been used as vaccines

Following the use of anti-idiotypic antibodies and the attendant limitations discussed above, the idiotypes of B lymphomas have been used as vaccines. In this approach, a patient’s idiotype is determined by polymerase chain reactions from the tumor tissues, and a synthetic idiotype, conjugated to a carrier such as keyhole limpet hemocyanin, is administered along with GM-CSF. A phase III trial in patients with follicular B lymphoma has been completed recently. Of the 117 patients who were in complete remission after chemotherapy, median time to relapse for the 76 vaccinated patients was 44.2 months, compared with 30.6 months for the 41 who received placebo. This was the first, and thus far, the only vaccine that has shown significant clinical activity in B cell lymphoma. For obvious reasons, this approach is limited to B lymphoma and related hematological malignancies.

Q. Which other group of cells is (theoretically) susceptible to anti-idiotypic targeting of tumor therapy?

A. The recombined T cell receptor is also expressed on specific clones of cells. The limitations that apply to the therapy of B cell lymphomas (mutation escape) also apply here, and it is in any case more difficult to generate antibodies to the T cell receptor.

Immunization with defined MHC I epitope does not lead to clinical benefit

The antigenic epitopes of differentiation antigens and cancer/testes antigens have been used extensively and several hundred patients with melanoma have been treated with these. Although anti-peptide CD8 responses have been detected in most studies, these have not generally translated into clinical benefit even for those patients who have shown good CD8 responses. A recent randomized trial using a gp100 peptide showed no evidence of clinical benefit.

Particularly interesting are efforts to vaccinate with altered peptide epitopes with higher affinity for the cognate T cell receptors. Immunization with such altered peptides is able to break tolerance against these self antigens where immunization with native peptides is not.

Q. What problem is intrinsic to this type of tumor therapy?

A. Immunization with differentiation antigens is premised on breaking tolerance and hence carries the near certainty of generating autoimmune responses (see Chapter 19).

This approach relies on the existence of a therapeutic window, which will permit anti-cancer immunity without debilitating autoimmunity.

Immunotherapy with DCs presenting a prostate antigen shows clinical benefit

In such studies, DCs are isolated from a cancer patient, pulsed with antigenic peptides, whole proteins, or tumor lysates and infused back into the patient. The most advanced clinical trials with this approach have been carried out in patients with prostate cancer, using the protein prostatic acid phosphatase because of the prostate-specific distribution of this protein, and because of its low homology with non-prostate proteins. Patients’ antigen presenting cells are pulsed with a fusion protein consisting of prostatic acid phosphatase and GM-CSF, and are re-infused into the patient. In a randomized Phase 3 trial in 512 subjects, prostate cancer patients who received the acid phosphatase pulsed autologous APCs (Sipuleucel-T) showed a median survival of 25.8 months as compared to 21.7 months for patients who received placebo. This trial formed the basis of the FDA approval of this treatment for patients with asymptomatic or minimally symptomatic prostate cancer.

Immunization with HSP–peptide complexes demonstrates clinical benefit

The role of HSP–peptide complexes in eliciting tumor immunity has been discussed earlier.

The successful murine studies have been translated into a series of phase I and II trials involving patients with pancreatic, gastric, stomach, and renal cancers, and with melanoma, B lymphoma, and chronic myelogenous leukemia.

In these trials, surgically obtained tumor specimens (or leukemia cells obtained by leukopheresis) from a given patient are used as the starting material for preparation of gp96–peptide or hsp70–peptide complexes specifically for that patient (Fig. 22.14).

Fig. 22.14 Treatment of cancer patients with HSP–peptide complexes

Surgically obtained tumor specimens from a given patient are used as the starting material for preparation of gp96–peptide or HSP70–peptide complexes specifically for that patient.

In a randomized phase 3 study in subjects with non-metastatic renal cell carcinoma, no difference was seen in recurrence-free survival between patients who received the autologous tumor-derived gp96–peptide vaccine (vitespen) and those who received no treatment. However, in the sub-set of patients with stage I and II disease the risk of recurrence among the 125 patients who received vitespen was approximately half the corresponding risk in 115 untreated patients (p=0.056). Moreover, in a sub-set of subjects with intermediate-risk disease the risk of recurrence among the patients who received vitespen was significantly reduced. Based on these data, the gp96–peptide vaccine vitespen was approved for use for intermediate-risk non-metastatic renal cell carcinoma patients in Russia.

Adoptive immunotherapy using T cells: the clinical benefits

Adoptive immunotherapy using T cells has a successful pedigree in murine models of cancer (Fig. 22.15). Clinical experience with bone marrow transplant recipients also provides a strong rationale for the approach.

Fig. 22.15 Adoptive immunotherapy with T cells

Lymphocytes removed from a patient with a tumor are expanded in vitro. Cells that recognize the tumor are selected and reinfused into the original patient. Adoptive therapy with allogeneic lymphocytes may also be carried out.

(Redrawn from Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003;3:666–675. Copyright 2002, Nature Reviews Cancer, Macmillan Magazines Ltd.)

Patients undergoing high-dose chemotherapy lose their bone marrow and are re-constituted with allogeneic stem cells, which engraft in the recipient. However, the T cells from the donor may see the normal tissues of the host as foreign, thus causing graft versus host disease (GVHD).

Interestingly, patients who develop GVHD also have a lower cancer relapse or graft versus tumor (GVT) incidence. The clinical experience with GVHD and GVT has long remained a compelling piece of evidence for the premise that T cells can eliminate human cancers in vivo (Fig. 22.16).