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Clean resection bed following removal of large mid body pancreatic tumor with minimal blood loss - Dr. What We DoEach patient is evaluated using a multidisciplinary approach and a team of cancer experts. We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer.
The allure of cancer immunotherapy as a potential magic bullet against cancer has intrigued researchers for over a century. Interest in this concept has waxed and waned over the past century and during this time the major advances in cancer therapy were focused on cytotoxic therapies and surgical excision. A recent publication summarizing results from the Society for Immunotherapy of Cancer (SITC) immunotherapy summit identifies nine critical hurdles in cancer immunotherapy (7).
One obstacle recently described by Lesterhuis and colleagues is that the timing and dosing for many immunotherapy regimens is often empirically derived and further refinement of these technical aspects may improve outcomes (8). An issue not identified by the SITC summit is that clinical cancer trials of new agents are typically undertaken in patients with widely metastatic disease who, due to the large burden of disease, the immunosuppressive activities of the tumor itself, or the immunosuppressive effects of prior therapies, are unable to respond to even a very effective immunotherapy. Another limitation of immunotherapy is the potential toxicity associated with many treatments.
The potential of cancer immunotherapy lies in the ability of the immune system to specifically distinguish and target non-self from self. To date, the focal point of cancer immunotherapy research has been T-cell biology and by default tumor antigen-specific immune responses. Given the existence of tumor antigens and their central importance in anti-cancer immunotherapy an approach being explored is the use of antigen-specific cancer vaccines. One potential shortcoming of cancer immunotherapy not detailed above is the need for antigen-specific immune responses. Although the reason for these findings is likely multi-factorial one of the most plausible explanations is that of immunoediting and antigen loss (Figure 1). In this sense, tumor heterogeneity is a major obstacle in that the tumor subclones which do not express a given antigen or have some other trait which makes them poorly immunogenic will be selected for after immunotherapy.
The atelectasis referred to here is that caused by bronchial obstruction, usually a tumor (i.e.
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Comparative Molecular Cytogenetics Core, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, USA. Department of Developmental Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China.
Present address: Department of Periodontology, Osaka University Graduate School of Dentistry, Yamadaoka, Suita-Osaka, Japan. Minimally invasive surgical techniques are used to decrease post-operative pain and speed up recovery. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button.
This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. The rationale underlying anti-cancer immunotherapy stems from the concept of immune surveillance first attributed to Erlich and colleagues over a century ago (1). Despite the continual advancement of the field, the inability to eradicate malignancy once it has disseminated remains the greatest challenge in cancer therapy. Of these nine critical hurdles, eight are related to the development of therapeutics and one is inherent to the therapies or diseases themselves. The lack of validated assays that can measure immune response across trials make it difficult to determine how strategies should be altered to improve efficacy. Ohashi and colleagues have shown that anti-tumor vaccination is most effective after surgical de-bulking of the primary tumor (13) demonstrating that an effective immunotherapy alone may be unable to induce a clinically significant response if tumor doubling time is short or tumor burden is high.
As we iatrogenically upset the delicate balance of the immune system we introduce the potential for severe adverse effects. Under the umbrella of this one category fall a broad number of biological issues that are the subject of intense scientific investigation and will ultimately, more so than any of the other hurdles listed above, dictate the utility of anti-cancer immunotherapy. Drawing on Erlichs earlier hypothesis, in the 1960s McFarlane Burnet and Lewis Thomas formally proposed the concept of immune surveillance as the true evolutionary purpose of the allograft tissue rejection response (27–29). Unfortunately, these vaccinations, although successful in generating an antigen-specific immune response, have failed to produce meaningful clinical responses. Despite the findings chronicled above demonstrating the promise and importance of antigen-specific immune responses in cancer immunotherapy, many problems exist with this approach.
As described by Schreiber and associates, this concept takes the principles of evolution and natural selection and applies them on a microscopic scale. Frontal radiograph of the chest (left) demonstrates indistinctness of the right heart border (white arrow) and slight elevation of the right hemidiaphragm from volume loss.
Individualized care is offered based on the patient's comorbid conditions, their tumor type, and its location.
Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes. This concept, founded in the idea that there is no evolutionary purpose to the tissue rejection immune response, states that tissue rejection is actually a manifestation of an immune surveillance mechanism that guards against spontaneously arising tumors. Over the past decade there has been a renaissance in cancer immunotherapy with a renewed belief by many that harnessing the immune system may be a viable strategy for successfully treating metastatic disease. Although the common thought with cytotoxic therapies is that the more that can be delivered, the greater the anti-tumor effect, this rationale may not hold true when trying to alter the delicate balance of the immune system for therapeutic gain. Although this article has recently generated attention in the lay media, its conclusions regarding the short-comings of mouse models have long been recognized by most researchers.


These issues need to be explored at the pre-clinical level but also as correlative studies in clinical trials.
Not surprisingly, some of the greatest successes of immunotherapy have been produced in pre-invasive or very early stage cancers where there is a limited volume of disease and patients have received minimal prior therapy. Some therapies can produce systemic inflammation and cytokine storm with disastrous effects.
They hypothesized that given the frequency of somatic mutations and that a proportion of these mutations will give rise to cells with malignant potential, then there must exist an evolutionary mechanism, likely immunological in nature, to deal with these potentially dangerous cells.
As mentioned above, sipuleucel-T (Provenge), a pulsed dendritic cell vaccine, uses the prostatic acid phosphatase antigen, although the precise mechanism of its clinical benefit remains uncertain.
The lateral view of the chest (right) shows downward displacement of the minor fissure (red arrow) and slight upward bowing of the major fissure (black arrow), both bordering the increased triangular density of the atelectatic middle lobe. In select cases, genetic analysis of the tumor is performed to search for drugs that can block important signaling pathways and thereby slow growth and kill cancer cells. In this review we explore some of the short-comings of cancer immunotherapy that have limited successful clinical translation. If such a mechanism does exist then it stands to reason that it can be re-invigorated and harnessed to battle malignancy in cancer patients. This renaissance has produced a seemingly exponentially increasing number of pre-clinical and clinical studies which are serving to translate this concept into the mainstream arsenal of anti-cancer therapeutics. Below we will consider some of these critical hurdles as well as other potentially critical obstacles. Issues such as exhaustion of effector cells and induction of suppressive networks must be considered.
Despite these short-comings, mouse models remain a staple of pre-clinical studies due to the complex mechanistic studies which can be performed, low cost, and short generation times amongst numerous other advantages.
Unfortunately, the capabilities of human immune monitoring fall short of the sophisticated assays used in pre-clinical models and further refinement and development are required (10). For example, intravesicular Bacille Calmette–Guerin is a standard of care in the management of non-muscle invasive bladder cancer demonstrating superiority to chemotherapy in this setting (14) and an HPV peptide vaccine demonstrated a 50% complete response rate in women with pre-invasive vulvar neoplasia (15). The systemic administration interleukin (IL)-2 has demonstrated activity against metastatic renal cell carcinoma and melanoma capable of producing durable responses in patients with metastatic disease, but toxicities can be so extreme that it limits its regular use and treatments are often provided in intensive care units. This killing relies on stress ligands such as NKG2D and recognition of TAA’s in the TCR-MHC complex. This implies that tumors, although derived from host tissues must have some unique property whereby they can be distinguished from self.
Another strategy being tested is the use of CARs that engineer T-cells with receptors specific for target specific tumor antigens.
They describe three processes: the first is elimination during which active immune surveillance finds and eradicates the majority of tumor cells (or all of the tumor cells when it is successful). We will give special consideration to what we consider the most formidable hurdle to successful cancer immunotherapy: tumor-induced immune suppression and immune escape. This idea, in its simplest form, is particularly attractive given that the immune system should be able to identify and specifically eradicate malignant cells based on the expression of abnormal antigens not expressed or present in normal tissues (2). Numerous strategies are being explored including augmentation of antigen-presenting cells (APC) and immune effector cells, immunologic stimulants such as cytokines and pathogen associated molecular pattern (PAMP) receptor agonists, adoptive transfer of transgenic immune cells, antibodies and molecules such as anti-CTLA-4 antibody or transforming growth factor (TGF)-beta antisense aimed at reversing suppressive mechanisms, and numerous vaccines comprised of DNA, peptides, or autologous tumor cells [reviewed in Ref. These authors, while acknowledging the many limitations of mouse models, do not endorse abandoning a model which has over many decades proven its utility in improving the understanding and treatment of human disease. In many human trials immune monitoring correlatives consist of a simple characterization of various markers in the peripheral blood.
In order to limit toxicity and mortality, such treatments are generally only undertaken at centers with expertise in IL-2 therapy but access to such centers is limited.
As a result of tumor heterogeneity, tumor cells which are less immunogenic or have up-regulated immunosuppressive factors are selected for.
This concept of tumor antigens was confirmed in experimental animal models by Old and Boyse in the 1960s (2) who demonstrated the existence of tumor-specific antigens in murine leukemias and mammary tumors. Few tumor-specific or tumor-associated antigens which can uniquely target malignant cells exist and those which do tend to be poorly immunogenic. As a tumor grows and invades surrounding tissues the release of inflammatory cytokines recruit components of the innate immune system which will in turn, via cytokines and in the draining lymph nodes, recruit an adaptive immune response.
We will discuss the need for antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as an Achilles heel of immunotherapy given tumor heterogeneity, immune editing, and antigen loss. Care must be taken, however, to make our pre-clinical models as robust and accurate as possible and to properly validate pre-clinical findings prior to clinical translation.
Mouse (11) and human (12) studies demonstrate that the immune response observed systemically may not be representative of what is occurring in the suppressed tumor microenvironment and draining lymph nodes.
Therapy can induce a severe vascular leak syndrome that emulates sepsis and is characterized by hypotension, vasodilation, pulmonary edema, neutrophil dysfunction, and, without intervention, culminates in end-organ failure and death (16, 17). More recently, a genetic analysis of human renal cell cancers likewise demonstrated similar variability (21).
These findings were later validated in human melanomas with the discovery of tumor-infiltrating lymphocytes able to recognize tumor antigens and lyse malignant cells (30).
Infusion of T-cells with CARs targeting the CD19 B-cell antigen in chronic lymphoid leukemia (32) or the NY-ESO-1 antigen in synovial cell sarcoma and melanoma (33) has demonstrated the ability to induce tumor regression. This is in direct contrast to microbes that express a vast array of proteins, lipids, and carbohydrates which are foreign and strongly immunogenic.
The second is dynamic equilibrium during which time the rapidly dividing and mutating tumor is being eliminated by the immune system that is simultaneously placing an evolutionary pressure on the tumor and selecting out variants which by virtue of poor immunogenicity or other mechanisms are able to survive the immune attack. Finally, we will discuss how combinatorial strategies may overcome some of the pitfalls of antigen specificity and highlight recent studies from our lab which suggest that the induction of antigen non-specific immune responses may also produce robust anti-tumor effects and bypass the need for antigen specificity. Two such therapies, sipuleucel-T, a pulsed dendritic cell vaccine (5), and ipilimumab, an anti-CTLA-4 antibody (6), have been amongst the first to be approved by the FDA for mainstream use (although some immunotherapies such as Bacilli Calmette–Guerin have been used clinically for decades without the fanfare of the aforementioned therapies).
Most mouse cancer studies are performed in young mice, however human cancers most commonly occurs in the aged and the use of aged mice would be more appropriate for cancer studies. Obviously, the ethical issues with justifying repeated biopsy of tumor or draining lymph nodes make this a dilemma, which is not easily resolved.


In addition to a systemic inflammation and cytokine storm, another concern with immunotherapy is the induction of immune responses which inappropriately target self or through bystander effects damage self tissues. Taking multiple spatially distinct biopsies from a single tumor the authors were able to demonstrate significant genetic changes within a given tumor providing evidence of the heterogeneity of even a single tumor. Tumor cells can secrete cytokines that recruit suppressive cells such as regulatory T (Treg) cells, immature myeloid cells [including immature dendritic cells (iDC) and myeloid-derived suppressor cells (MDSC)], and M2 macrophages. It has been implicated that even therapies that are not necessarily billed as antigen-specific ultimately rely on the generation of antigen-specific T-cell responses for clinical effect.
Nonetheless, some tumor antigens do exist and as demonstrated above immunity against them can be generated. In the third phase, escape, tumor subclones which are poorly recognized or eliminated by the immune system are able to grow unchecked and become clinically observable disease. These two therapies, which provide overall survival benefits in castration-resistant prostate cancer and melanoma respectively, have generated enthusiasm and played a central role in re-introducing immunotherapy into the mainstream. This is particularly relevant for immunotherapy studies given the significant changes in immune functioning with age. This autoimmunity is seen in certain instances in patients treated with ipilimumab, where therapy disrupts the immune suppressive mechanism network that prevents anti-cancer immune responses but also usefully prevents inappropriate immune responses. The concept of tumor antigens has since evolved from tumor-specific antigens to tumor-associated antigens. For example, clinical studies of CTLA-4 blockade with ipilimumab, which is aimed at reversing immune suppression, correlate clinical effect with the generation of T-cells specific to the NY-ESO-1 (34) and Melan-A (35) antigens. The studies above also outline that even when a target antigen is identified and a response is generated, it may fail to translate into clinical benefit. Experimental evidence from this same group demonstrates that tumors generated under selective immune pressure are less immunogenic (39). In a series of studies examining immunotherapy in young versus aged mice we have demonstrated a significant impact of age on efficacy and toxicity (submitted). Disruption of the latter can produce autoimmune colitis, dermatitis, hepatitis, endocrinopathy, and other adverse effects (18). M2 macrophages and MDSC inhibit T-cell responses through a variety of mechanisms, including nutrient sequestration via arginase, reactive oxygen species (ROS) generation, nitric oxide (NO), as well as interference with trafficking into the tumor site. Similarly, Fong and colleagues demonstrate that clinical response of prostate cancer patients to ipilimumab is also correlated with the robustness of antigen-specific antibody and T-cell responses (36).
Sipuleucel-T provides no statistical benefit in freedom from progression and improves median overall survival by about 16 weeks (5). We suggest use of aged mice should be considered as part of the pre-clinical development of any cancer study.
Immunosuppressive cytokines and the up-regulation of immunosuppressive enzymes [like indolamine-2,3-dioxygenase (IDO) and arginase] that catabolize essential nutrients required for effector cell activation and also produce immunosuppressive catabolites, contribute to a microenvironment where immune responses are difficult to instigate and sustain. If tumors can become less immunogenic during carcinogenesis due to selective pressure from the immune system then it stands to reason that once established they can also evolve less immunogenic phenotypes if exposed to a new selective pressure from the immune system, as would occur with immunotherapy. We also suggest that companion animals with spontaneous tumors provide an excellent platform for validating pre-clinical studies prior to human translation. Immunoediting is discussed in a separate section below and we will discuss the concept of tumor-induced immune suppression here (22, 23). Furthermore tumor cells will down-regulate MHC molecules, loose expression of antigenic molecules, and up-regulate inhibitory molecules such as PD-L1. Clinically, this concept is confirmed by the loss of the MART-1 antigen in melanoma patients after adoptive transfer of MART-1 specific T-cells (40, 41). Thus, although these therapies may validate the concept of cancer immunotherapy and are an important first step, they fall short of the theorized potential of eradicating metastatic disease. The hostile nature of the tumor microenvironment and numerous mechanisms underlying this are well documented.
In addition to antigen loss, there is evidence that tumor cells also down regulate the ability to present antigen, either by down-regulating major histocompatibility complex (MHC) or antigen processing capabilities (42, 43). Unfortunately, to date, clinical studies of cancer immunotherapy have failed to manifest the pre-clinical and theoretical promise of this approach. The immune system is in a delicate balance of fluxes of activation and suppression that allow for appropriate responses but guard against potentially harmful responses that are inappropriate either in scale or target. Also supporting this hypothesis, it has been demonstrated that the patients who respond to antigen-specific therapies, such as a MUC-1 peptide pulsed dendritic cell vaccine, are those who have epitope spreading where an immune response is generated against tumor antigens not targeted by the antigen-specific therapy (44). In this manuscript we will review some of the hurdles of cancer immunotherapy including the need to overcome tumor-induced immune suppression and immune escape. The adverse effects observed within this recent trial highlights the critical need to assess the short-comings of our pre-clinical models as a means to better foreshadow toxicity responses within the clinic. A spectrum of suppressive cells, such as immature dendritic cells, regulatory T (Treg)-cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are actively recruited to or generated within the tumor microenvironment (Figure 1). This may be one mechanism whereby antigen-specific therapies can overcome this shortcoming and it may be that only those patients who are able to overcome the outgrowth of tumor subclones which poorly express MUC-1 are able to produce a clinically meaningful response, although this is not conclusively demonstrated. We will discuss the importance of inducing antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as a major potential pitfall of immunotherapy given tumor heterogeneity, immune editing, and antigen loss.
Likewise, a mélange of suppressive cytokines and enzymes, secreted by the tumor itself or resulting from the chronic inflammation associated with many tumors, contributes to the recruitment of the suppressive cells listed above and to direct suppression of effector cells.
Cytokines such as TGF-beta, IL-10, and prostaglandin (PG)-E2 with documented immune suppressive effects may be highly expressed (24).
Enzymes such as indolamine-2,3-dioxygenase (IDO) and arginase, which catabolize tryptophan and arginine respectively, can create a microenvironment in which immune effectors cannot activate or proliferate and suppressive cells thrive (25, 26). Tumor lumps (arrows) and control injection sites 30 d after the injection are shown (left). They function to both deplete the aforementioned amino acids essential for effector cell activity but also produce catabolites which can be independently suppressive and can alter the phenotype of immune cells from activating to suppressive (25, 26).



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