William B. Coley, MD, now known as the Father of Immunotherapy, first attempted to harness the immune system for treating cancer in the late 19th century. Having noted a number of cases in which patients with cancer went into spontaneous remission after developing erysipelas, he began injecting mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens into patients&rsquo; tumors in 1891.

Coley achieved responses such as durable complete remission in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. The lack of a known mechanism of action for &lsquo;Coley&rsquo;s toxins&rsquo; and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments early in the 20th century.

The strategy of using attenuated bacteria to treat malignancies resurfaced in 1976 when a trial was conducted to test the use of the tuberculosis vaccine Bacille Calmette-Gu&eacute;rin (BCG) as a means of preventing the recurrence of nonmuscle invasive bladder cancer.

BCG therapy was very effective and continues to be used today.

James P. Allison, PhD, Discusses Future Immune Checkpoint Strategies

Allison is the director of the immunotherapy platform at The University of Texas MD Anderson Cancer Center.

The idea of using immunotherapy in cancer, in general, returned to prominence when Thomas and Burnet first proposed the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes acted as sentinels to identify and eliminate somatic cells transformed by spontaneous mutations.

The absence of data supporting the existence of tumor-specific antigens and the technical inability to culture and manipulate lymphocytes in vitro postponed further progress in this area for some time.

The T-cell growth factor interleukin 2 (IL-2) was identified in 1976,

allowing investigators to culture T cells in vitro for the first time. Large doses of IL-2 were shown to be effective when administered to patients with established, metastatic cancers by enhancing T-cell production.

The use of IL-2 as an immunotherapeutic agent eventually gained US Food and Drug Administration (FDA) approval in metastatic kidney cancer in 1991, and in metastatic melanoma in 1998.

In the 1970s, Milstein and K&ouml;hler pioneered the production of monoclonal antibodies in the laboratory using hybridomas, antibody-secreting cell lines formed by the fusion of lymphocytes with myeloma cell lines.

Research on antibody-based therapies eventually led to the development of rituximab, which binds to CD20 on the surface of immature B cells and targets them for elimination by natural killer cells.

The first monoclonal antibody approved by the FDA for the treatment of a cancer, non-Hodgkin&rsquo;s lymphoma, came in 1997.

In 1991, researchers cloned a melanoma-derived antigen that could induce a response from cytotoxic T cells.

In 2007, Olivera J. Finn, PhD, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania described this paper as &ldquo;the molecular divide between the &lsquo;old&rsquo; human tumor immunology that postulated but could not prove the existence of tumor antigens (Ags) and the &lsquo;new&rsquo; tumor immunology that uses these Ags and genes that encode them to understand tumor immunity and design effective immunotherapy.&rdquo;

Clinically effective vaccines remained elusive, however, until 2010, when the FDA approved the first cancer vaccine, sipuleucel-T, for castration-resistant prostate cancer. This dendritic cell vaccine was able to extend overall survival of patients in clinical trials, although it did not have any effect on the time to disease progression.

There are several emerging trends in immuno-oncology, including checkpoint inhibitors and adoptive T-cell therapy (ACT). Immune checkpoint componentssuch as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1)&mdash;are expressed on tumor-infiltrating lymphocytes and many types of tumor cells, and they allow malignant cells to evade cytotoxic immune responses. Ipilimumab, an antibody targeting CTLA-4 approved by the FDA for use in patients with melanoma, inhibits this process and facilitates T-cell activation against tumor cells. Antibodies targeting PD-1 and PD-L1 are also being tested in phase III trials against several types of tumors. This year in Japan nivolumab became the first PD-1 inhibitor to achieve regulatory approval in melanoma. Promising results have also been posted for the experimental anti-PD-L1 antibody MPDL3280A in melanoma, lung cancer, and bladder cancer.

William B. Coley, MD injected live and inactivated Streptococcus pyogenes and Serratia marcescens into patients&rsquo; tumors in 1891 to try to harness the immune system in the treatment of cancer.

Lack of a known MOA for &lsquo;Coley&rsquo;s toxins&rsquo; and the risks of infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments.

In the 1970s, large doses of IL-2 were shown to be effective when administered to patients with established, metastatic cancers by enhancing T-cell production.

In 2010, the FDA approved the first cancer vaccine, sipuleucel-T, for castration-resistant prostate cancer.

In 2011, Ipilimumab, an antibody targeting CTLA-4 was approved by the FDA for use in patients with melanoma.

In 2014, in Japan nivolumab became the first PD-1 inhibitor to achieve regulatory approval in melanoma.

Promising results have also been posted for the experimental anti-PD-L1 antibody MPDL3280A in melanoma, lung cancer, and bladder cancer.

In ACT, T cells activated against tumor-specific antigens are isolated from the patient, expanded ex vivo, and then reintroduced into the patient. A phase I study presented at the 2014 ASCO Annual Meeting tested human papillomavirus (HPV)-specific T cells in patients with metastatic cervical cancer and produced several durable complete responses.

&ldquo;Clearly, the ability to manipulate components of the immune system with drugs and to manipulate and activate an individual patient&rsquo;s cells in the laboratory are the areas with great interest and activity now,&rdquo; said Clifford A. Hudis, MD, the chief of breast cancer medicine service at Memorial Sloan Kettering Cancer Center in New York City, although he warned that clinicians should avoid creating unreasonable expectations among patients.

&ldquo;The key point physicians have to convey to lay audiences is the power of the immune system and the fact that manipulating it can cause significant toxicities that require expert management. It is not as simple as stimulating the immune system,&rsquo; a misleading phrase that many patients find attractive,&rdquo; Hudis stated.

Decker WK, Safdar A. Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley&rsquo;s legacy revisited.

Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors.

Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape.

Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.

Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.

Milstein C. The hybridoma revolution: an offshoot of basic research.

Rudnicka D, Oszmiana A, Finch DK, et al. Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity.

van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.

Finn OJ. Human tumor immunology at the molecular divide.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.

Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC).

Hinrichs CS, Stevanovic S, Draper L et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.

Articles

Clinical Articles

William B. Coley, MD, now known as the Father of Immunotherapy, first attempted to harness the immune system for treating cancer in the late 19th century.

A Brief History of Immunotherapy

With the emergence of new immunotherapeutic agents for treating cancer, there is a growing need for the identification of biomarkers that will allow clinicians to take full advantage of these treatments. Biomarkers are needed to fulfill several important roles in immuno-oncology, both before and after treatment.

Biomarker testing prior to initial treatment is needed to predict both the efficacy and toxicity of a given treatment option in a particular patient. This would allow clinicians to avoid unnecessary ineffective treatments and help alert both the oncologist and patient to possible serious adverse effects (AEs) before they arise so that a management plan can be made. Pretreatment biomarkers can be classified as either prognostic markers that provide information on the future course of the disease, or predictive markers that identify patients likely to respond or suffer severe AEs from a given treatment. A proposed classification system, the Immunoscore, uses two markers (CD8 and CD3) at different places in the tumor as prognostic biomarkers, and is being validated in colon cancer.

After treatment, biomarkers are needed that will allow accurate measurement of a patient&rsquo;s response to therapy. Conventional imaging benchmarks for solid tumors, such as the Response Evaluation Criteria in Solid Tumors (RECIST) or the World Health Organization (WHO) criteria, are often not useful for determining responses to immunotherapies. This lack of utility can occur with immuno-oncology treatments that prolong survival without reducing tumor progression, or in cases where lymphocyte infiltration increases tumor size. Post-treatment biomarkers that directly assay immune activation either at the tumor site or in the blood are therefore more useful for monitoring treatment response.

There are several important considerations for the development of clinically relevant biomarkers in immuno-oncology. Given the complexity of interactions between the immune system and tumor cells, it is likely that a number of different biomarkers will need to be tested in tandem to produce an informative profile.

Markers present in peripheral blood and serum are more desirable for ease of serial analysis over the course of a treatment, and the issues of sample processing and storage are crucial to reducing the amount of variability introduced by handling. Moreover, the testing method used must also be accurate, precise, and reproducible enough to allow for comparisons across different laboratories at different times.

The challenges of identifying predictive biomarkers in immunotherapy are illustrated in results from several clinical trials of cell checkpoint inhibitors. Programmed cell death-1 (PD-1) and its ligand, PD-L1, are promising targets of immunotherapies; however, their suitability as predictive biomarkers is still unclear. PD-L1 is expressed in several different cancers, including breast cancer, lung cancer, and melanoma, and is the target of several inhibitors now being developed. However, data presented at the 2014 ASCO Annual Meeting showed that the rate of PD-L1positive cancer cells in a collection of tissue samples was 50% or less in most tumor types examined.

The development of immune-oncology treatments has increased the need for predictive and prognostic biomarkers.

PD-1/PD-L1 status needs to be evaluated before embarking on clinical trial enrollment to inform the patient recruitment process.

Transcriptome analysis, flow cytometry, and protein microarrays are being used to overcome the limitations of single markers in immunotherapy.

&ldquo;PD-1 and PD-L1 markers are not elevated at the same levels across all cancer types, meaning that the effectiveness of the anti-PD-1 immunomodulatory agents may depend on specific elevation levels,&rdquo; noted one of the study&rsquo;s authors, Zoran Gatalica, MD, DSc, executive medical director of Caris Life Sciences, a leading biosciences company that provides broad tumor profiling and biomarker analysis for therapeutic associations for non-small cell lung cancer.

&ldquo;Moreover, immunotherapies are not appropriate for every solid tumor; some tumors are not associated with these specific immune responses. PD-1/PD-L1 status, however, should be evaluated before embarking on clinical trial enrollment, because this analysis can significantly inform the patient recruitment process, and can be done easily and inexpensively via gold-standard immunohistochemistry testing,&rdquo;

Several methods are being used to overcome the limitations of single markers in immunotherapy, including transcriptome analysis, flow cytometry, and protein microarrays. The Immuno-Oncology assay from Response Genetics, another life sciences company engaged in the research and development of clinical diagnostic tests for cancer, is an immune-focused transcriptional assay designed to facilitate biomarker discovery in clinical trials. These technologies allow investigators in clinical trials to monitor many different potential biomarkers simultaneously to increase predictive reliability and to identify informative markers in an unbiased manner.

In a phase II trial of ipilimumab, an anti-CTLA-4 antibody, investigators used gene expression profiling in pretreatment and post-treatment tumor samples to identify transcriptional profiles associated with clinical activity of the treatment.

High levels of immune-related genes before treatment were correlated with a greater probability of response. Further studies examining this greater pool of immune-related markers may be able to overcome the uncertainty present when a single marker is used.

The use of specific antibodies in peripheral blood as predictive biomarkers would be very desirable in the clinical setting. Blood samples are easy to collect and store, and multiple samples can be taken over the course of a treatment. Protein microarrays have proven to be a useful tool for measuring the circulating levels of specific antibodies. Investigators used this technology to determine the specific antibody responses induced by a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting whole cell immunotherapy in a clinical trial in patients with prostate cancer.

The production of antibodies against T-cell alternative reading frame protein (TARP), a protein associated with prostate cancer initiation, was correlated with increased survival time. This result demonstrates the potential for protein microarrays as biomarker assays. &emsp;

Although many trials for new immunotherapies are under way, there is an absence of biomarker assays that are validated, informative, and reliable. Better patient stratification and monitoring using biomarkers would benefit not only clinical applications of immuno-oncology, but also the development of new therapies. The renewed emphasis on biomarker identification is a necessary step to unlocking the full potential of cancer immunotherapies.

Galon J, Pag&egrave;s F, Marincola FM, et al. Cancer classification using the Immunoscore: a worldwide task force.

Morse MA, Osada T, Hobeika A, Patel S, Lyerly HK. Biomarkers and correlative endpoints for immunotherapy trials.

. 2013. doi: 10.1200/EdBook_AM.2013.33.e287.

Butterfield LH, Palucka AK, Britten CM, et al. Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers.

Gatalica Z, Ghazalpour A, Holterman D, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type.

Caris Life Sciences web site. Caris Life Sciences Research Provides Key Clinical Insights on Immunotherapeutic Targets in a Broad Range of Cancers [press release]. http://www.carislifesciences.com/news/caris-life-sciences-research-provides-key-clinical-insights-on-immunotherapeutic-targets-in-a-broad-range-of-cancers. Accessed July 29, 2014.

Guhathakurta D, Sheikh NA, Meagher TC, Letarte S, Trager JB. Applications of systems biology in cancer immunotherapy: from target discovery to biomarkers of clinical outcome.

Ji RR, Chasalow SD, Wang L et al. An immune-active tumor microenvironment favors clinical response to ipilimumab.

Nguyen MC, Tu GH, Koprivnikar KE, Gonzalez-Edick M, Jooss KU, Harding TC. Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy.

Biomarkers are needed to fulfill several important roles in immuno-oncology, both before and after treatment.

Better Biomarker Testing Needed in Immuno-Oncology

Using the patient&rsquo;s immune system to target and destroy cancer cells has long been a sought-after goal in oncology, because such an approach would have considerable advantage over conventional therapies by sparing normal cells and by maintaining immune surveillance and memory to more effectively prevent cancer recurrences.

Many strategies that have shown promise in the preclinical setting, however, have frequently been disappointing in clinical trials, and the process of developing and applying the ideal cancer-specific immunotherapy in the clinic remains challenging.

&ldquo;The idea of being able to vaccinate a patient against their cancer seems so tantalizingly simple, given the overwhelming success of preventative vaccines against infectious pathogens,&rdquo; said Christopher A. Klebanoff, MD, assistant clinical investigator at the Center for Cancer Research of the National Cancer Institute and the National Institutes of Health in Washington, DC.

Jedd D. Wolchok, MD, PhD, on the Management of Side Effects Associated With Immunotherapies

Wolchok is a medical oncologist at Memorial Sloan Kettering Cancer Center.

&ldquo;Unfortunately, high-quality clinical data supporting [the idea] that therapeutic cancer vaccines can be effective have been extremely limited, as the field is all too aware,&rdquo; Klebanoff stated. He explained that there are many reasons why therapeutic cancer vaccines might fail.

&ldquo;The tumor microenvironment can be highly immune-suppressive because of regulatory T cells and other immune-suppressive factors, such as expression of the co-inhibitory ligand (programmed death receptor ligand 1) PD-L1 on tumor cells and stroma. Additionally, the tumor-specific T-cell repertoire can be immunologically exhausted or even senescent. Finally, generating a sufficient number of tumor-reactive T cells to combat a rapidly growing tumor is not easy, particularly given the problems of immune suppression and immune exhaustion,&rdquo; Klebanoff said.

Klebanoff explained that &ldquo;T cells can be radically potent,&rdquo; mediating, in some cases, regression of every last cancer cell in some patients. He cautioned, however, that with such potency comes the possibility for toxicity.

&ldquo;Unfortunately, the field has already experienced severe, and in some cases lethal, toxicities from immunotherapies targeting shared antigens between tumors and normal tissues, such as HER2/neu,&rdquo; Klebanoff said. Because tumors frequently express an array of antigens that may not be specific to the tumor alone, the potential for autoimmunity exists, and therefore, collateral damage to normal tissues.

Autoimmunity may be induced by so-called adoptive immunotherapy approaches, whereby immune cells are stimulated and expanded in vitro and then reintroduced into the patient to provide immediate antitumor therapy.

Some of the adverse events (AEs) caused by this type of immunotherapy include colitis, liver and lung toxicity, and vitiligo.

Autoimmunity may also be induced by the use of exogenously administered monoclonal antibodies, for example, those that are designed to remove critical inhibitory checkpoints of the immune system (eg; anticytotoxic T-lymphocyte antigen 4 [CTLA-4]). AEs that have been observed in this regard include arthritis, hypothyroidism, colitis, and vitiligo.

Investigators have therefore sought to identify tumor-associated antigens (TAAs), such as MAGE-1, which is not expressed in most normal adult tissues and can be recognized by cytotoxic T-lymphocytes (CTLs) to use as vaccines.

&ldquo;As the adage goes, prevention is the best medicine. Ideally, this means choosing to target antigens which are uniquely expressed on cancers, but not normal tissues,&rdquo; Klebanoff said. He explained that such targets could include unique epitopes generated from tumor-specific mutations, so-called cancer testis antigens that are only expressed on tumors, or viral-associated antigens such as those found in oncogenic viruses like human papillomavirus.

&ldquo;As I and others in my group see it, this is one of the most pressing issues limiting the wide dissemination of T-cell immunotherapies to a broad range of cancers: finding suitable targets,&rdquo; he said, noting how the use of new technologies has helped in this regard.

&ldquo;The ability to quickly and cheaply sequence genomes means it is now possible to sequence a patient&rsquo;s tumor and specifically look for tumor-specific antigens generated from mutations to target immunologically. Targeting tumor-specific mutations, ideally driver mutationsbut in practice any consistently expressed mutations would do&mdash;is perhaps the best way to ensure tumor-specificity without placing normal tissues at risk,&rdquo; Klebanoff stated. He also noted the real possibility for highly selective T-cell therapies targeted at specific tumor markers to be more readily accessible in the future, such as cancer-testis antigen NY-ESO-1. &emsp;

Vaccine-based therapies for cancer have often met with limited clinical success.

Klebanoff noted, however, that this could, in part, be attributed to the design of clinical trials. &ldquo;For patients and oncologists alike, the only meaningful endpoint is whether a therapeutic approach, immunologic or otherwise, can demonstrably extend life. To accurately assess this, a trial must have an adequately sized, contemporaneous control arm to which the treatment is compared.&rdquo; He suggested that the only successful trial using this measure is the sipuleucel-T trial in prostate cancer reported by Kantoff and coworkers in 2010, and he further noted that even the results of the trial have remained controversial.

High-quality clinical data supporting the efficacy of cancer vaccines has been limited.

Because tumors frequently express an array of antigens not specific to the tumor, potential for autoimmunity exists, and therefore, collateral damage to normal tissues.

Increasing knowledge about immunotherapies presents an opportunity for further improvement and refinement of strategy

Combining vaccines with therapies to inhibit tumor-derived immuno-inhibitory signals may be one means of improving efficacy of vaccine-based immunotherapies.

&ldquo;Ultimately, the painful reality is that most vaccine-based immunotherapies have not performed well by these measures,&rdquo; Klebanoff stated. &ldquo;The reasons for failure [of vaccine-based therapies] are multifactorial, but as I see it, are mostly due to the fundamental problems of host immune-suppression, T-cell exhaustion, and a handicapped kinetics race between T cells and the tumor,&rdquo; Klebanoff said.

Indeed, many factors, such as the nature of the patient population studied, work against the efficacy of cancer vaccines; patients in such trials often have end-stage disease with poor performance status, and may lack sufficient immune function (for example, owing to old age or the use of prior anticancer therapies) to mount an effective antitumor response.

Klebanoff also emphasized the differences in growth kinetics between the tumor and the attacking T cells, which must be overcome for a vaccine to be effective. Moreover, tumors have also evolved mechanisms to promote tolerance and evade immune detection, and the in vivo microenvironment around the tumor may significantly reduce the efficacy of such vaccines. For these reasons, combining vaccines with therapies to inhibit tumor-derived immuno-inhibitory signals may be one means of improving their efficacy.

Despite the lack of improvement in efficacy for vaccine-based cancer therapies as described in a 2011 review,

the increasing knowledge about immunotherapies presents an opportunity for further improvement and refinement of strategy, according to Klebanoff. He also predicted a more widespread availability in the future of technologies such as chimeric antigen receptor (CAR) therapy, a treatment designed to make a patient&rsquo;s own T cells more effectively target tumor cells.

&ldquo;I think a clear path forward is to game the system in our patient&rsquo;s favor using adoptive T-cell immunotherapy. Each of the potential obstacles to successhost immune suppression, T-cell exhaustion, tumor growth versus T-cell growth kinetics&mdash;can be optimized with this approach. Prior host conditioning before cell infusion can disrupt the immune-suppressive environment, expansion of T cells ex vivo and selection of defined T-cell subsets can combat the issues related to T-cell exhaustion, and infusing up to 1 &times; 10

antitumor T cells clearly can tilt the kinetic race,&rdquo; Klebanoff stated.

Aldrich JF, Lowe DB, Shearer MH, Winn RE, Jumper CA, Kennedy RC. Vaccines and immunotherapeutics for the treatment of malignant disease.

. 2010;2010:697158. doi: 10.1155/2010/697158.

Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer.

Janikashvili N, Larmonier N, Katsanis E. Personalized dendritic cell-based tumor immunotherapy.

Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet?

Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Kono K. Current status of cancer immunotherapy.

Using the patientâ€™s immune system to target and destroy cancer cells has long been a sought-after goal in oncology.

Autoimmunity and Limitations of Cancer Vaccines

Gregory A. Daniels, MD, PhD, associate clinical professor of medicine, Division of Hematology-Oncology, University of California, San Diego, discusses opportunities to combine immunotherapies with both targeted therapies and other immunotherapies. Daniels references the results of the 2007-2012 PROCLAIM National Registry, which was presented at the 2014 ASCO Annual Meeting.

Gregory A. Daniels, MD, PhD, discusses opportunities to combine immunotherapies with both targeted therapies and other immunotherapies.

Combining Immunotherapies With Targeted Therapies and Other Immunotherapies

Jedd D. Wolchok, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the management of side effects associated with immunotherapies.

View more about managing side effects and the limitations of immunotherapies > >

Jedd D. Wolchok, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the management of side effects associated with immunotherapies.


The Management of Side Effects Associated With Immunotherapies

Advances in our understanding of critical immunomodulatory checkpoints, such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), have led to some recent notable successes in the immunotherapy of cancer.

An example is ipilimumab, a humanized monoclonal antibody directed against CTLA-4, which has been shown to significantly prolong survival when used as monotherapy in patients with advanced melanoma.

Nivolumab, another checkpoint inhibitor, which blocks the programmed death receptor 1 (PD-1) on activated T-cells, is also under investigation as an immunotherapy in cancer.

Another successful immunotherapy is sipuleucel-T; this immunotherapy entails patient-derived peripheral blood mononuclear cells and antigen-presenting cells, which have been activated ex vivo by prostatic acid phosphatase, and the immune activator granulocyte-macrophage colony-stimulating factor (GM-CSF).

This treatment has prolonged survival in men with metastatic castration-resistant prostate cancer (mCRPC).

In a recent panel discussion, Roy S. Herbst, MD, PhD, from the Yale Cancer Center, noted the potential for immunotherapies such as nivolumab to be used in combination with targeted therapies.

Gregory A. Daniels, MD, PhD, on Combining Immunotherapies

Daniels is a professor of medicine at University of California, San Diego.

&ldquo;We have an agent [nivolumab] that&rsquo;s going to become a backbone now for combination with some of the other targeted therapies that we use,&rdquo; Herbst predicted.

Discussing the rationale for immunotherapy combinations in non-small cell lung cancer (NSCLC), Karen L Reckamp, MD, MS, at City of Hope and Beckman Research Institute, in Southern California, said that &ldquo;harnessing the immune system is not just about the tumor cell&hellip; it&rsquo;s about the microenvironment and what&rsquo;s happening there, and we know that the microenvironment promotes metastatic disease, and progression, and so blocking some of those things may be attacking a part of the cancer we&rsquo;ve been ignoring.&rdquo;

A phase III study has investigated the safety and efficacy of dacarbazine, a standard chemotherapy treatment for advanced melanoma, in combination with ipilimumab,  compared with dacarbazine alone.

The results showed that the ipilimumab combination was significantly better than dacarbazine alone in prolonging overall survival (OS), with a hazard ratio (HR) for death of 0.72 (

<.001), and the benefit was observed for the combination across all of the subgroups examined.

The disease control rate (defined as complete [CR] or partial response [PR] or stable disease) did not differ significantly between the combination and the dacarbazine-alone groups (33.2% vs 30.2%;

=.41); however, the median duration of response (among those with CR or PR) was 19.3 months and 8.1 months, respectively (

=.03), indicating durable objective responses achieved with the ipilimumab combination. There were significantly more grade 3/4 adverse events (AEs) in the combination arm (56.3% vs 27.5%;

<.001). Although AEs were largely as expected with either therapy, elevated liver function test results were identified  more frequently with the combination.

Because they have distinct mechanisms of action, there was also good rationale for the combination of ipilimumab with vemurafenib, a targeted inhibitor of BRAF

mutation, which is also approved for the treatment of advanced melanoma.

This phase I study, however, was closed after use of the 2 agents at the approved doses resulted in grade 3 elevations in aminotransferase levels. Although these hepatic events were asymptomatic and reversible with drug discontinuation or glucocorticoid treatment, the findings highlight the need for appropriately conducted clinical trials to evaluate the safety of such combinations.

Ipilimumab and nivolumab are believed to target complementary immuno-inhibitory pathways leading to enhanced T-cell activation, and thus there is rational basis for combining these 2 immunotherapies. Results of a phase I study demonstrated a confirmed objective response rate of 40% (21 of 52 patients) in concurrently treated patients, which was higher than that historically seen with either agent alone, and the combination was associated with a manageable safety profile.

In view of these initial findings, a phase III study (CheckMate 067) is now investigating the safety and efficacy of nivolumab either alone or in combination with ipilimumab, or ipilimumab alone, in patients with previously untreated advanced melanoma.

The primary endpoint is OS, with secondary endpoints of progression free survival (PFS) and overall response rate (ORR). The estimated completion date for the primary outcome measure is October 2016.

A phase I, open-label, single-center, dose-escalation study was initiated to determine the safety of combining ipilimumab with prostate GVAX, (a GM-CSF gene-transfected tumor cell vaccine) in men with mCRPC.

The results of this small study showed the combination of ipilimumab (3.0 mg/kg) with GVAX to be safe and tolerable in this patient population; the most common AEs were injection site reaction, fatigue, and pyrexia. A 50% or greater decrease in prostate-specific antigen (PSA) was noted in 7 patients (25%) who had received a 3.0 mg or 5.0 mg dose of ipilimumab.

Studies are also assessing ipilimumab in combination with other prostate cancer therapies, including abiraterone/prednisone,

for their potential use in men with advanced or mCRPC.

In addition to sipuleucel-T, immunotherapies for prostate cancer include the PROSTVAC vaccines (viral-based vaccines that are thought to enhance the T-cell response to PSA).

A phase I, dose-escalation trial of PROSTVAC in combination with ipilimumab reported no dose-limiting toxicities among 30 patients, and the combination did not seem to increase immune-related AEs over ipilimumab alone.

Although the trial was too small to evaluate efficacy of the combination, 58% of patients who were chemotherapy na&iuml;ve had PSA declines, and the trial provided proof of concept for this type of combination therapy in prostate cancer.

Sipuleucel-T in combination with ipilimumab is also under investigation in a phase I study of advanced prostate cancer,

and in a phase II study with either delayed or immediate ipilimumab treatment in mCRPC.

Lung cancer is another area of investigation for immunotherapy combinations. CheckMate 012

is a phase I study investigating nivolumab as monotherapy or in combination with multiple therapies in patients with stage IIIB/IV NSCLC, including platinum-based chemotherapies (gemcitabine/cisplatin, pemetrexed/cisplatin, carboplatin/paclitaxel), antiangiogenesis therapy (bevacizumab), and epidermal growth factor receptor (EGFR)-targeted agents (erlotinib); the study will also investigate the combination of nivolumab with ipilimumab in this patient population. The use of ipilimumab in combination with mutation-targeted therapies (crizotinib or erlotinib) is being investigated in a phase I trial of patients with stage IV NSCLC with corresponding mutations; the overall goal is to evaluate a recommended phase II dose and to assess short- and long-term toxicities of these combinations.

A phase II study is also investigating the use of ipilimumab in combination with conventional chemotherapy (carboplatin and etoposide) in patients with small cell lung cancer; the primary outcome is PFS at 1 year.

A phase III study is investigating ipilimumab (or placebo) in combination with paclitaxel and carboplatin in subjects with stage IV/recurrent squamous NSCLC; the estimated primary completion date for this trial is October 2015.

Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma.

Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Novel Immunotherapy Combinations in NSCLC. Available at:

http://www.onclive.com/peer-exchange/nsclc-therapies/Novel-Immunotherapy-Combinations-in-NSCLC

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

van den Eertwegh AJ, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

The Next Wave in Immunotherapy: Combinations

James P. Allison, PhD, director, immunotherapy platform, The University of Texas MD Anderson Cancer Center, discusses the future of immune checkpoint strategies.

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Future Immune Checkpoint Strategies

The development of new immunotherapies for cancer treatment generated significant interest at the 2014 ASCO Annual Meeting, particularly checkpoint inhibitors targeting the programmed cell death-1 (PD-1) receptor and its ligand, PD-L1. Some of the most intriguing results came from trials in bladder cancer, a disease that has not had a significant treatment advance in 30 years.

Daniel P. Petrylak, MD, is a professor of medicine and medical oncology and director of prostate and genitourinary medical oncology at Yale Cancer Center in New Haven, Connecticut. He is the senior author of a multicenter, phase I study evaluating an investigational anti-PD-L1 antibody in patients with advanced bladder cancer who did not respond to other treatments.

recently spoke with Petrylak about the renewed interest in using immunotherapy to treat advanced bladder cancer.

Q: Bacillus Calmette-Gu&eacute;rin (BCG) therapy for superficial urothelial bladder cancer (UBC), the first US Food and Drug Administration-approved immunotherapy, was introduced nearly 40 years ago. Why has immunotherapy for bladder cancer remained static for so long, and why has it become a hot topic once again in 2014?

A: Immunotherapy is in the spotlight now because some of the targets for the newer checkpoint inhibitors have been identified in locally advanced and metastatic disease, and we really didn&rsquo;t have any treatments that targeted those particular agents in the past. So we know that PD-1 and PD ligand are expressed both in bladder cancer cells as well as on the infiltrating immune cells, and we just simply didn&rsquo;t have drugs that targeted those particular immune checkpoints.

Q: Would you expect these agents to be effective in a wide variety of tumors, or are checkpoint inhibitors particularly suited to bladder cancer?

A: Checkpoint inhibitors are not just specific to this cancer. Bladder cancer was selected for study based on identification of immune targets, as well as on the fact that there has been no major advance in this cancer in 30 years. We knew from experience with superficial disease that BCG therapy had activity, so it made a lot of sense. Immune checkpoint inhibition therapy has already demonstrated activity in tumors such as non-small cell lung cancer (NSCLC),

renal cell carcinoma, and melanoma. In fact, there was just an approval in Japan for an anti-PD-1 antibody, nivolumab, for patients with melanoma.

Q: Does BCG therapy work through a mechanism related to immune checkpoint molecules such as PD-1 and PD-L1?

A: That&rsquo;s a good question, and nobody knows the answer yet. The response to BCG is multifactorial, but it may be through a similar mechanism to checkpoint inhibitors. It&rsquo;s hard to determine.

Q: Are there any prospects for making improvements to the BCG regimen in the near term?

A: Clearly, studies need to be done with the checkpoint inhibitors in addition to BCG or in patients where BCG has failed. Those are things being discussed and I believe need to be done.

Q: You were an investigator in a phase I trial of MPDL3280A, an antibody targeting PD-L1, in metastatic UBC.

What are the advantages of this immunotherapeutic agent over the present standard of care?

A: This study was conducted with patients with metastatic UBC who had failed prior chemotherapy, and there is no standard therapy for these patients now. This is certainly a group that needs new treatment options. Response rates are 10% to 20% with cytotoxic agents among this population, whereas they are much higher, at 42% overall, in this trial. In contrast to cytotoxic therapy, the side effects with the anti-PD-L1 antibody are significantly less.

Q: Are there any plans to investigate MPDL3280A as a first-line therapy?

A: There is now no standard of care for metastatic platinum-ineligible urothelial cancer. Although there are no supporting phase III data, gemcitabine and carboplatin are commonly used to treat patients with metastatic UBC who are ineligible to receive cisplatin. The phase II trial of MDPL3280A is looking at 2 groups of patients: those who are platinum-ineligible with no prior chemotherapy, and those who are platinum-refractory.

Thus, these platinum ineligible-patients will be treated upfront with immunotherapy.

Q: The trial results showed that 11% of patients with tumors identified as PD-L1 negative responded to MPDL3280A. What are the hypotheses for why those patients achieved a response?

A: Several different factors may be involved. One is that the biomarker testing in this trial, for the most part, was done on archival tissue. Thus, if the primary specimen was obtained 2 or 3 treatments removed from the patient&rsquo;s current status, those samples may not be indicative of the current interaction between the tumor and the patient&rsquo;s immune system. That may be part of the explanation. The other explanation is that resistance to these drugs is probably multifactorial, and PD ligand expression may be part of the story but not the whole story.

Q: Are there any other promising immunotherapeutic agents being developed for use in bladder cancer?

A: Evaluations are under way for anti-PD-1 antibodies, the anticytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, and there are some novel combination trials that are going on with checkpoint inhibitors. I think that this is a very fruitful area of investigation. It&rsquo;s a totally new area of investigation. The ultimate question is how these agents will be sequenced with chemotherapy.

Q: Are there any new immunotherapeutic agents with the potential to treat muscle-invasive bladder cancer?

A: The current standard for muscle-invasive UBC is cytotoxic chemotherapy. We need to understand more about how and why patients progress. I think that there is a potential for it. Certainly, these agents need to be evaluated both as adjuvants and neoadjuvants in high-risk patients.

Q: Where do you think that immunotherapy is going, and what role will it play in the treatment of bladder cancer 10 years from now?

A: I think that it plays a significant role. There are always going to be several different treatments that you&rsquo;ll need to effectively treat cancer, whether a combination of chemotherapy and immune therapy, or some other combination. The optimal sequences of these agents with surgery, chemotherapy, and immunotherapy will be defined through clinical trials.

Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors

Clinicaltrials.gov. A Study of MPDL3280A in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer.

http://clinicaltrials.gov/ct2/show/study/NCT02108652

The development of new immunotherapies for cancer treatment generated significant interest at the 2014 ASCO Annual Meeting, particularly checkpoint inhibitors targeting the PD-1 receptor and its ligand, PD-L1. 

Immunotherapy (Issue 3) | Special Reports