Immune-based Cancer Therapies Research Articles

Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy.

The ability of immune-based cancer therapies to elicit beneficial CD8(+) CTLs is limited by tolerance pathways that inactivate tumor-specific CD4 Th cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 Th cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8(+) CTL priming as long as the cognate epitopes are linked via presentation on the same dendritic cell. In this study, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that provide help via the above-mentioned classical linked pathway, as well as provide nonlinked help that facilitates CTL function in T cells not directly responding to cognate Ag. We found that engagement of tumor-unrelated CD4 Th cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual costimulated helper cells are themselves helped by a CD134(+) cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B(+) effector CD8 T cells and a reciprocal decrease in Foxp3(+)CD4(+) cell frequency. Notably, the tumor-unrelated CD4 Th cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the antitumor response.

IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy.

Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Rα. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rβγ, IL-15 does not bind IL-2Rα and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2Rα. Mechanistically, IL-2Rα sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Rα endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Rα expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies.

Cancer Vaccination and Targeting Nanog for Enhanced CTL-Mediated Immune Response

Evasion of the immune-mediated cytotoxicity is an all too common hallmark of cancer. A recent study revealed that cancer vaccination - through the establishment of tumor reactive CD8+ CTLs- drives the evolution of tumor cells toward an immune-resistant and stem-like phenotype and they identified the transcription factor Nanog as a pivotal player in this process. Tellingly, the suppression of Nanog expression via using Nanog siRNA renders tumour cells more sensitive to immune response and leads to reduction of tumour growth. Taken together, the results of these studies support the notion that inhibiting Nanog may have therapeutic implications with respect to immune-based cancer therapy.

MDSCs in cancer: Conceiving new prognostic and therapeutic targets

The incomplete clinical efficacy of anti-tumor immunotherapy can depend on the presence of an immunosuppressive environment in the host that supports tumor progression. Tumor-derived cytokines and growth factors induce an altered hematopoiesis that modifies the myeloid cell differentiation process, promoting proliferation and expansion of cells with immunosuppressive skills, namely myeloid derived suppressor cells (MDSCs). MDSCs promote tumor growth not only by shaping immune responses towards tumor tolerance, but also by supporting several processes necessary for the neoplastic progression such as tumor angiogenesis, cancer stemness, and metastasis dissemination. Thus, MDSC targeting represents a promising tool to eliminate host immune dysfunctions and increase the efficacy of immune-based cancer therapies.

Abstract 1342: A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells

Abstract Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has become clear that in order for immune-based cancer therapy to be successful, the major obstacle of immune tolerance to tumor self-antigen must be overcome. Here we report a strategy to accomplish this by engineering molecular events at the interface between antigen peptide-MHC (pMHC) and TCR. In particular, our approach is based on fusion of pMHC to the protein annexin V (ANXA5), which behaves as a ‘dynamic anchor’. The dynamic anchor, in a synchronized and synergistic manner, couples the early onset of TCR signaling by cognate pMHC with a boost in pMHC-TCR affinity, with serial pMHC binding, and with extensive TCR crosslinking. In our system, the dynamic anchor is linked to pMHC and strongly attaches to the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. This anchor in turn exerts a mechanical force that stabilizes interactions at the pMHC-TCR interface. Furthermore, once the dynamic anchor attaches to these T cells, it facilitates repeated, serial pMHC binding and quickly arranges into uniform 2D matrices, thereby prompting TCR crosslinking. We found that fusion of ANXA5 to pMHC augments activation of cognate T cells by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to a new class of vaccination that can raise a robust immune response against low affinity tumor self-antigen. Citation Format: Chih-Ping Mao, Chien-Fu Hung, TC Wu. A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2015-1342

Abstract B59: Transnuclear mice as models of the immune response to pancreatic cancer

Abstract Somatic cell nuclear transfer (SCNT) allows the efficient generation of mice that will serve as a source of T cells of defined specificity. By harvesting primary T cells from animals that are at the peak of an anti-tumor response, and by transfer of the nucleus from such antigen specific T cells into an enucleated oocyte, embryonic stem cells that harbor the TCR rearrangements of that T cell may be obtained and used for the construction of cloned mice. These animals contain T cells of the appropriate tumor specificity, have no genetic alterations other than the physiological TCR rearrangements and are the closest approximation of the tumor-specific CTLs that contribute to tumor resolution in vivo. Importantly, the generation of transnuclear mice is rapid, requiring approximately 6 weeks from T cell harvest to obtaining chimeric animals. No good animal models are available for studying the immune response to pancreatic cancer, unlike in melanoma and prostate cancer for which we have excellent models. We are addressing this problem by generating a panel of transnuclear mice from pancreatic tumor infiltrating CD4 and CD8 T cells. These mice will 1) allow us to characterize the optimal CD8 and CD4 immune response necessary for rejection of pancreatic tumors; 2) define the spectrum of antigens seen by pancreatic tumor-infiltrating regulatory T cells; 3) address possible synergy of anti-tumor CD8 T cells with costimulatory blockade, silencing of anergy-related genes, or combination therapy with small molecule based chemotherapy; and 4) generate further interest in the community for studying immune-based therapies for pancreatic cancer. One of the best characterized pancreatic tumor antigens in both mice and humans is mesothelin. We have generated a TN mouse line from a mesothelin-specific CD8 T cell. However, the resulting mouse shows downregulation of CD8 in the thymus, and produces CD8 T cells that are functionally anergic. This anergy can be overcome by prolonged culture with anti-CD3/CD28 coated beads, and the resulting activated Mes358 TN cells accumulate in the pancreatic tumor environment and block the early stages of pancreatic tumor growth. As a second approach, we used CRISPR technology to generate mesothelin-/- mice. When immunized with mesothelin, these mice will provide a robust source of Mes358 tetramer+ CD8 T cells for use as a donor population for SCNT to generate a second line of mesothelin-specific TN mice with higher affinity for mesothelin. Immune-based therapies show a variable degree of success across different tumor types, with melanoma being highly amenable to anti-CTLA and other checkpoint blockade therapies while pancreatic cancer has been more refractory although combination of Ipilimumab with GVAX has shown modest efficacy. Many factors could contribute to this disparity, notably stroma and poor vascular density that limit drug delivery to pancreatic tumors. Understanding the requirements for CD8 T cell priming, trafficking and function in the context of stromal depletion is likely key to the success or failure of immunotherapies for pancreatic cancer. Citation Format: Stephanie K. Dougan, Angelina Bilate, Rudolf Jaenisch, Hidde L. Ploegh. Transnuclear mice as models of the immune response to pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B59.

Immune-based therapies for childhood cancer.

After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in B-ALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms.

P08.04 * LEPTOMENINGEAL CARCINOMATOSIS VS LEPTOMENINGEAL LYMPHOMATOSIS: COMPARISON OF THE CEREBROSPINAL FLUID INFLAMMATORY CELLS

BACKGROUND: The inflammatory-cell infiltrate surrounding solid tumours is progressively gaining importance, in an attempt to reach a better understanding of the pathophysiology of the disease, and also improve future design of immune-based cancer therapies. However, information about the inflammatory cell populations in leptomeningeal disease is scarce. STUDY DESIGN: We have studied the distribution of the main inflammatory cell populations in the cerebrospinal fluid (CSF) from 83 patients diagnosed with leptomeningeal carcinomatosis (LC, n = 65) and lymphomatosis (LyM, n = 18). These samples were matched with CSF samples from another set of patients diagnosed with similar epithelial-cell carcinomas (n = 36), and diffuse B-cell high-grade lymphoma (n = 19), but without leptomeningeal involvement. Patients with infectious or inflammatory diseases were excluded from this study. Diagnosis of leptomeningeal disease was established on the basis of clinical symptoms, CSF cytology, magnetic resonance images and/or CSF biochemical data. METHODS: Flow cytometry immunophenotyping (FCI) was used to describe the percentage of lymphocytes, monocytes and polymorphonuclear cells (PMN) in the CSF samples on the basis of their forward and side-scatter characteristics. Only CSF samples without red-cell contamination entered the study. RESULTS: No differences in the distribution by sex, age, volume of CSF sample received, absolute CSF cell-count, and levels of CSF glucose and protein was found between patients with LC and LyM. Median (interquartile) CSF inflammatory cells/mm3 was 7.96 (2.5-17.6) in LC, and 2.71 (1.2-6.9) in LyM (p = 0.043). Median (interquartile) rates of lymphocytes, monocytes and PMN cells were 59.7% (35-76.6), 24% (16-53) and 1.5% (0-7.6) in LC, and 98.5% (70.8-100), 1.5% (0-29.3), and 0% in LyM (p 1% PMN in 38/65 samples; p= 0.002). CONCLUSIONS: A different inflammatory cell background was seen in the CSF from patients with LyM and LC. CSF samples from patients with LC had a higher number of inflammatory cells and a recurrent description of PMN cells, a distinctive parameter not found in patients with LyM and cancer patients without LC. Further studies are warranted to determine the significance of these exploratory findings.

Current concepts in the diagnosis and management of cytokine release syndrome

AbstractAs immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.

From bench to bedside: immunotherapy for prostate cancer.

The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.

Clinical experience with live-attenuated, double-deleted (LADD) listeria monocytogenes targeting mesothelin-expressing tumors

Meeting abstracts Immune-based cancer therapies have demonstrated benefit in multiple clinical trials. The interest in using recombinant bacteria as vaccine vectors for active cancer immunotherapy derives in part from their ability to stimulate multiple innate immune pathways and, at the same time

FOXO3 regulates tumor-associated DC tolerogenicity by binding and sequestering NF-kB. (P2037)

Abstract Tumor-associated dendritic cells (TADC) are a major contributor of immune tolerance in the tumor microenvironment. We previously reported that the transcription factor FOXO3 is a critical mediator of TADC tolerogenicity and that silencing Foxo3 expression promoted anti-tumor immunity. In the current study, we sought to identify the mechanism by which FOXO3 regulates TADC function. It was previously reported that FOXO3 to inhibits NF-kB activity in T cells through the transcriptional regulation of IkB proteins. In contrast, our data demonstrate that unlike in non-DC populations, FOXO3 was principally detected in the cytoplasm of TADC. Further analysis revealed that despite extensive phosphorylation, cytoplasmic FOXO3 was stable. These findings suggested that FOXO3 may not solely function as a transcriptional regulator. Instead, our findings show for the first time that FOXO3 binds both the RelA and p50 NF-kB subunits and sequesters them to the cytoplasm. The formation of this protein complex prevents nuclear translocation and downstream pro-inflammatory signaling by NF-kB. In the absence of FOXO3, NF-kB re-localizes to the nucleus and turns on expression of pro-inflammatory genes. We further demonstrate that NF-kB enhances cytoplasmic FOXO3 stability. These new insights into the regulation of DC tolerogenicity provide new potential targets for the enhancement of immune-based therapies for cancer, where FOXO3 may reduce pro-inflammatory activities of TADC.

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.

Computational Methods in Linear B-cell Epitope Prediction

known as antigens. It has great pattern recognition capability that may be used to distinguish between foreign cells entering the body (non- self or antigen) and the body cells (self). Any substance like proteins, polysaccharides, lipoproteins, polypeptides, nucleoproteins and nucleic acids that can induce the immune system to produce a corresponding antibody is called an antigen. This ability of antigen is called antigenicity. That portion of the antigen which can bind with the antigen binding site of the antibody is called B-cell epitope or antigenic determinant. B-cell epitopes can be linear or conformational. These epitopes play a vital role in the development of peptide vaccines, in diagnosis of diseases, immune based cancer therapies and also for allergy research. Since experimental methods of identifying epitopes are costly and time consuming, computational methods for prediction are desirable. This paper reviews various approaches like amino acid scale based methods and machine learning methods used for the prediction of linear B-cell epitopes.

Chemoimmunotherapy: reengineering tumor immunity

Cancer chemotherapy drugs have long been considered immune suppressive. However, more recent data indicate that some cytotoxic drugs effectively treat cancer in part by facilitating an immune response to the tumor when given at the standard dose and schedule. These drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. In addition, cancer chemotherapy drugs can promote tumor immunity through ancillary and largely unappreciated immunologic effects on both the malignant and normal host cells present within the tumor microenvironment. These more subtle immunomodulatory effects are dependent on the drug itself, its dose, and its schedule in relation to an immune-based intervention. The recent approvals of two new immune-based therapies for prostate cancer and melanoma herald a new era in cancer treatment and have led to heightened interest in immunotherapy as a valid approach to cancer treatment. A detailed understanding of the cellular and molecular basis of interactions between chemotherapy drugs and the immune system is essential for devising the optimal strategy for integrating new immune-based therapies into the standard of care for various cancers, resulting in the greatest long-term clinical benefit for cancer patients.

Focus on the target: the tumor microenvironment, Society for Immunotherapy of Cancer Annual Meeting Workshop, October 24th-25th 2012

The Workshop associated with the 27th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), North Bethesda, MD, October 24-25, 2012 focused on targeting the tumor microenvironment as part of an integrative approach to immune-based cancer therapy.

Integrative oncology meets immunotherapy: New prospects for combination therapy grounded in Eastern medical knowledge

As cancer rates rise globally, standard care is being questioned; new approaches involving immune therapies are emerging. With this shift comes a corresponding shift in the use and potential of herbal medicines and extracts. The focus of this article, which has evolved from a presentation at the Second Beijing International Symposium on Integrative Medicine (BISIM May 19-20, 2012), is particularly on Chinese medicine, but is generalizable to Eastern medicine more broadly and to other herbal traditions. Until recently, herbal and related treatments have been used as adjuvants to conventional care - for reducing side-effects, enhancing cytotoxicity, and sometimes, undesirably counteracting the efficacy of chemotherapy and radiation. Now, in the context of a new class of immune-based cancer therapies, herbal and other complementary modalities are looked at as enhancers of the body's immunity.

Caloric restriction responses can maintain immune responses during aging (47.14)

Abstract Age-related defects accumulate in both the innate and adaptive arms of immunity to generate a state of immune deficiency. Our laboratory has previously shown a decrease in immune responses in aged mice compared to younger mice in the context of OX40 costimulation. This loss of immunity during aging underscores the need for simple approaches to boost immunity in older individuals. We hypothesize that immune responses in the context of OX40 activation or blockade of CTLA-4 in older mice can be restored and/or maintained through caloric restriction (CR) or dietary supplementation with a CR mimetic. Two CR dietary regimens were used to determine if immunity in old immune-compromised mice could be restored and if immunity could be maintained during aging. In addition mice were fed diets that were formulated with resveratrol (100 ppm), a CR mimetic. Tumor immune responses and Ag-specific T cell responses in these mice were then assessed and compared to young mice and the appropriate dietary controls. Our results demonstrate that caloric restriction cannot restore immune function in old mice. However, CR or resveratrol dietary supplementation initiated at a young age can maintain both OX40-mediated anti-tumor immunity and T cell responses as these mice age. Thus, the induction of a caloric restriction response (via traditional CR or by a CR mimetic) appears to maintain immunological fitness and may increase the effectiveness of immune-based cancer therapies in older subjects.

Abstract 3540: Prostate cancer-infiltrating mast cells suppress anti-tumor immunity through a TGFβ and IL-13 dependent mechanism

Abstract Immune suppression is a major obstacle in the design of successful immune-based therapies for cancer. Using an experimental model of prostate cancer, we previously demonstrated the rapid induction of tolerance and suppressive activity in adoptively transferred tumor antigen-specific cytotoxic T cells. The mechanism of this tolerance induction involved T cell interactions with tumor-associated dendritic cells (TADCs) which express elevated levels of the forkhead box protein, FOXO3. We now propose a mechanism by which tumor-infiltrating mast cells exert immune suppressive activity on both T cells and DCs. Mast cells were identified as approximately 30% of the total CD45+ tumor-infiltrating leukocytes and were capable of degranulation and promoting immune suppression. Purified tumor-associated mast cells (TA-MC) spontaneously secreted IL-13 and TGF-β which were further increased by FcαR cross-linking or LPS stimulation. The suppression of Ag-specific T cells and the development of tolerogenic DC were found to be dependent on TA-MC secretion of TGF-β and IL-13 during in vitro co-culture. Further, blocking IL-13 and TGF-β in vivo prevented the induction of DC tolerogenicity and the induction of T cell tolerance, which, in turn, resulted in reduced tumor burden. Our findings reveal novel mast cell-mediated mechanisms that favor immune tolerance over anti-tumor immunity and therefore provide promising targets for the enhancement of cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3540. doi:1538-7445.AM2012-3540

Re-purposing cancer therapeutics for breast cancer immunotherapy

After decades of work to develop immune-based therapies for cancer, the first drugs designed specifically to engage the host anti-tumor immune response for therapeutic benefit were recently approved for clinical use. Sipuleucel-T, a vaccine for advanced prostate cancer, and ipilimumab, a monoclonal antibody that mitigates the negative impact of cytotoxic T lymphocyte antigen-4 signaling on tumor immunity, provide a modest clinical benefit in some patients. The arrival of these drugs in the clinic is a significant advance that we can capitalize on for even better clinical outcomes. The strategic and scientifically rational integration of vaccines and other direct immunomodulators with standard cancer therapeutics should lead to therapeutic synergy and high rates of tumor rejection. This review focuses on the use of cyclophosphamide, doxorubicin, and HER-2-specific monoclonal antibodies to dissect mechanisms of immune tolerance relevant to breast cancer patients and illustrates how appropriate preclinical models can powerfully inform clinical translation. The immune-modulating activity of targeted, pathway-specific, small molecule therapeutics is also discussed. Fully understanding how cancer drugs impact the immune system should lead to the ultimate personalized cancer medicine: effective combinatorial immunotherapy strategies that simultaneously target signaling pathways essential for tumor growth and progression, and systematically break multiple, distinct immune tolerance pathways to maximize tumor rejection and effect cure.