Opportunities For Immunotherapy Research Articles

Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy

It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.

Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency.

Immune checkpoint inhibition is a new therapeutic strategy that has shown promising efficacy in many cancer types. Significant activity associated with mismatch repair (MMR) deficiency has been observed in hypermutated, microsatellite unstable (MSI) metastatic colorectal cancer (CRC). Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 (POLD1) or DNA polymerase E (POLE) alterations cause a hypermutated phenotype in CRC. This recently identified and rare subgroup of proficient-MMR tumors may also benefit from immunotherapy. In this review, we provide a comprehensive overview of recent data on CRC tumors harboring POLD1 or POLE mutations, with a focus on their molecular, histological, and clinical features. We also examine the evidence supporting the development of immune checkpoint inhibitors in this specific subgroup of CRC patients.

Checkpoint Proteins in Pediatric Brain and Extracranial Solid Tumors: Opportunities for Immunotherapy.

Pediatric brain and extracranial solid tumors are a diverse group of malignancies that represent almost half of all pediatric cancers. Standard therapy includes various combinations of surgery, cytotoxic chemotherapy, and radiation, which can be very harmful to a developing child, and survivors carry a substantial burden of long-term morbidities. Although these therapies have improved survival rates for children with solid tumors, outcomes still remain extremely poor for subsets of patients. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function have been described. When found on malignant cells or in the tumor microenvironment, they contribute to immune evasion and tumor escape. Agents designed to inhibit these proteins have demonstrated significant efficacy in human adult solid tumor studies. However, there is limited research focusing on immune checkpoint molecules and inhibitors in pediatric solid tumors. In this review, we examine the current knowledge on immune checkpoint proteins with an emphasis on cytotoxic T lymphocyte antigen-4 (CTLA-4); programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1); OX-2 membrane glycoprotein (CD200); and indoleamine 2,3-dioxygenase (IDO). We review T-cell signaling, the mechanisms of action of these checkpoint molecules, pediatric preclinical studies on checkpoint proteins and checkpoint blockade, pediatric checkpoint inhibitor clinical trials conducted to date, and future immunotherapy opportunities for childhood cancers. Clin Cancer Res; 23(2); 342-50. ©2016 AACR.

Opportunities for immunotherapy in microsatellite instable colorectal cancer.

Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC.

Opportunities in immunotherapy of ovarian cancer

Ovarian cancer (OC) is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival, the 5-year survival rates remain ominously low at 45%. Novel therapies are urgently needed. The presence of T cells in the OC tumor microenvironment is correlated with improved progression-free and overall survival, while the presence of regulatory T cells and expression of T-cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy could hold promise in improving the treatment of OC. In this review, we will discuss the rational of immunotherapy, highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and summarize the immune effects of selected chemotherapeutic and radiotherapeutic agents.

One-Shot Immunomodulatory Nanodiamond Agents for Cancer Immunotherapy.

The use of functional nanodiamonds (fNDs) to deliver CpG oligonucleotides (ODNs) for sustained immunostimulation is reported. It is demonstrated that monotherapy using this immunostimulatory agent significantly suppresses the tumor growth in two murine tumor models. This fND-based nanoagent opens new opportunities for immunotherapy, as well as clinical applications of various types of therapeutic nucleic acids.

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study.

Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention.

Abstract A081: A PD-L1-targeted Probody provides antitumor efficacy while minimizing induction of systemic autoimmunity

Abstract Antibodies to T cell checkpoint molecules like PD-1, PD-L1 and CTLA-4 can unleash potent and durable anti-tumor immunity in many different cancer types. These drugs induce anti-tumor immune responses by activating T cells in tumors, but because similar mechanisms control anti-tumor immunity and self-tolerance, they can also induce systemic autoimmunity by activating autoreactive T cells in normal tissues. Combinations of checkpoint inhibitors greatly increase clinical responses, but similarly increase these toxicities, thereby limiting their clinical utility. New methods are therefore needed that provide anti-tumor activity without deregulating systemic immunity. Probody™ therapeutics are recombinant, proteolytically-activated antibody prodrugs, designed to widen therapeutic index by minimizing interaction with normal tissue and maximizing interaction with tumor. Probodies exploit the fundamental dysregulation of extracellular protease activity that exists in tumors relative to healthy tissue. The amino terminus of the antibody light chain is extended with a protease-cleavable linker and a masking peptide designed to block antigen binding to the antibody. Cleavage of the linker by specific tumor-associated proteases leads to dissociation of the mask and release of an antibody competent to bind to antigen in the tumor. Probodies bind only minimally to antigen in healthy tissue because there are insufficient active proteases present to remove the mask. The feasibility of the Probody approach to checkpoint targets is supported by preclinical studies in which intratumoral delivery of low dose immune modulators enables durable, systemic anti-tumor responses despite negligible systemic exposure. Here we demonstrate the ability of a Probody targeting PD-L1 to provide equivalent anti-tumor efficacy in mice to that of its antibody parent, while minimizing induction of systemic autoimmunity. A mouse/human cross-reactive anti-PD-L1 antibody was generated by phage display, and engineered into a Probody. Binding to mouse PD-L1 by the Probody in its masked state was significantly reduced relative to its binding following proteolytic removal of the mask. The presence of active proteases capable of releasing the Probody's mask was demonstrated in frozen sections of MC38 and CT26 murine syngeneic tumors. Systemic administration of the PD-L1 Probody to mice bearing established MC38 syngeneic tumors induced anti-tumor efficacy comparable to the unmasked parental antibody at the same dose. In contrast, the PD-L1 Probody provided protection from induction of autoimmune diabetes in NOD mice at doses sufficient to induce maximal diabetes with the parental antibody. Finally, PD-L1 occupancy by the Probody on peripheral blood and splenic T cells was significantly reduced compared to that of the parental antibody at the same dose. This finding is consistent with the reduced ability of the Probody in its masked form to bind to PD-L1 and to induce autoimmunity outside of the tumor. By demonstrating equivalent efficacy with an improved safety profile, these results provide validation of the Probody concept for a T cell checkpoint target. Probodies should expand opportunities for immunotherapies, particularly those that are limited by enhanced toxicities when used in combination. Citation Format: Chihunt Wong, Li Mei, Kenneth R. Wong, Elizabeth E.M. Menendez, Olga Vasiljeva, Jennifer H. Richardson, James W. West, Michael Kavanaugh, Bryan A. Irving. A PD-L1-targeted Probody provides antitumor efficacy while minimizing induction of systemic autoimmunity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A081.

Abstract 2485: Novel monoclonal antibody targeting cancer stem cells

Abstract Caerus Therapeutics (Caerus) is developing a monoclonal antibody directed to a cancer specific epitope on CD66c (CEACAM6) designated 109.12. CD66c has been shown in preclinical studies to be expressed on the colorectal cancer stem cell population but not on normal intestinal stem cells, making this a potential target for a therapeutic antibody. Previous attempts by other companies to develop anti-CD66c antibodies were unsuccessful due to cross-reactivity with CD66c on normal tissues. Caerus has developed a monoclonal antibody to a cancer-specific, glycan epitope that is only expressed in the adult during malignant transformation, enabling the targeting of CD66c on both cancer stem cells (CSCs) as well as bulk tumor without cross-reactivity with CD66c on normal cells. The glycan epitope recognized by the antibody has a novel structure not previously described that is highly protein-specific and site-specific. The specificity is due to a unique dual-recognition determinant for the site-specific glycosylation. In addition to its expression on colorectal tumorspheres, the epitope recognized by the 109.12 antibody is expressed by a wide variety of cancers including colon, pancreatic, lung stomach and a subtype of breast cancer. The biological role of CD66c in malignancy and tumor dissemination is well documented; the specificity of the antibody for a CD66c epitope only expressed in malignant cells offers multiple opportunities for immunotherapy and diagnosis of a diverse spectrum of cancers. Citation Format: Jeff Holderness, Amy Turner, Sam dolezal, Steve Wolpe, Michael Pierce, Cohava Gelber. Novel monoclonal antibody targeting cancer stem 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 2485. doi:10.1158/1538-7445.AM2015-2485

Impact of disease heterogeneity on treatment efficacy of immunotherapy in Type 1 diabetes: different shades of gray.

Type 1 diabetes results from selective destruction of insulin-producing pancreatic β-cells by a progressive autoimmune process. Type 1 diabetes proves very heterogeneous in pathology, disease progression and efficacy of therapeutic intervention. Indeed, several immunotherapies that appear ineffective for the entire treated patient population in fact look promising in subgroups of patients. It therefore seems inconceivable that one standard therapy will provide the golden bullet of disease intervention. Instead, personalized medicine may improve immune intervention efficacy rates. We discuss the effect of disease heterogeneity on treatment outcome of immunotherapies, identifying apparent gaps in our understanding of treatment efficacy in subgroups of Type 1 diabetic patients as well as identifying future opportunities for immunotherapy.

Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy.

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.

Epicutaneous exposure to proteins and skin immune function

The skin has a sophisticated and highly orchestrated immune system. The ability of proteins encountered at skin surfaces to access that immune system remains controversial, however. In this article the question considered is whether proteins encountered epicutaneously (on the skin) at abraded or tape-stripped skin surfaces, but also at sites where the skin is intact, can engage with the cutaneous immune system to provoke and regulate responses. The available evidence suggests that epicutaneous exposure to foreign proteins is able to elicit immune and allergic responses, and that encounter with protein via this route may favour the development of selective Th2 responses and allergic sensitisation. It is also clear that proteins can modify immunological function when delivered topically and that intact skin may provide an effective route of exposure for active immunotherapy of allergic disease. An appreciation that epicutaneously applied proteins can interact with the skin immune system, even when delivered at intact skin sites, opens up important opportunities for immunotherapy, local immune modulation and the treatment of inflammatory skin diseases. It also indicates that this route of exposure must be considered as part of the safety assessment and risk management of protein-induced allergic sensitisation.

Abstract IA25: Immunotherapy opportunities and challenges in ovarian cancer

Abstract Epithelial ovarian cancer (EOC) cells are antigenic and express a multitude of proteins that have been validated as known tumor-associated antigens (TAAs) including Her-2/neu, p53, NY-ESO-1, cdr2, hTERT, mesothelin, survivin, SP-17, WT1 and others. Clinical data indicate that the immune system affects the outcome of patients with EOC; the presence of intraepithelial tumor-infiltrating lymphocytes correlates with improved progression-free and overall survival, as shown by numerous correlative studies conducted on hundreds of ovarian cancer samples. Tumor infiltrating lymphocytes (TILs) isolated from ovarian cancers are oligoclonal, recognize autologous tumor, are specific to known TAAs ex vivo, and exhibit tumor-specific cytolytic activity. Tumor-specific T-cell precursors can also be detected in the blood of patients with advanced ovarian carcinoma. These observations suggest that activation of antitumor immunity could be feasible and could produce clinical results in patients with EOC. To date, immunotherapy investigations with intraperitoneal IL-2 infusion, CTLA-4 antibody, vaccines using NY-ESO-1 peptide, virus-modified autologous tumor cells, or dendritic cells (DCs) pulsed with whole autologous tumor lysate have yielded limited but encouraging results in EOC. We will review lessons from previous studies and will discuss various opportunities and challenges in the development of effective immunotherapy for EOC. Citation Format: George Coukos. Immunotherapy opportunities and challenges in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA25.

Modifications of Microvascular EC Surface Modulate Phototoxicity of a Porphycene anti-ICAM-1 Immunoconjugate; Therapeutic Implications

Inflammation and shear stress can upregulate expression of cellular adhesion molecules in endothelial cells (EC). The modified EC surface becomes a mediating interface between the circulating blood elements and the endothelium, and grants opportunity for immunotherapy. In photodynamic therapy (PDT), immunotargeting might overcome the lack of selectivity of currently used sensitizers. In this study, we hypothesized that differential ICAM-1 expression modulates the effects of a drug targeted to surface ICAM-1. A novel porphycene-anti-ICAM-1 conjugate was synthesized and applied to treat endothelial cells from macro and microvasculature. Results show that the conjugate induces phototoxicity in inflamed, but not in healthy, microvascular EC. Conversely, macrovascular EC exhibited phototoxicity regardless of their state. These findings have two major implications; the relevance of ICAM-1 as a modulator of drug effects in microvasculature, and the potential of the porphycene bioconjugate as a promising novel PDT agent.

Pathological Mobilization and Activities of Dendritic Cells in Tumor-Bearing Hosts: Challenges and Opportunities for Immunotherapy of Cancer

A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor’s ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach.

Immunotherapy for Head and Neck Cancer Patients: Shifting the Balance

Head and neck squamous cell carcinoma is the sixth most common cancer in the western world. Over the last few decades little improvement has been made to increase the relatively low 5-year survival rate. This calls for novel and improved therapies. Here, we describe opportunities in immunotherapy for head and neck cancer patients and hurdles yet to be overcome. Viruses are involved in a subset of head and neck squamous cell carcinoma cases. The incidence of HPV-related head and neck cancer is increasing and is a distinctly different disease from other head and neck carcinomas. Virus-induced tumors express viral antigens that are good targets for immunotherapeutic treatment options. The type of immunotherapeutic treatment, either active or passive, should be selected depending on the HPV status of the tumor and the immune status of the patient.

Assessing Potential Genotoxicity of Sleeping Beauty Transposition Events in T-Cell Immunotherapy by Supercomputer-Based High Throughput Profiling,

Abstract 4174The first-in-human clinical trial using Sleeping Beauty (SB) transposition for T-cell immunotherapy is under way at the University of Texas MD Anderson Cancer Center. To understand potential genotoxic risks involved in our non-viral SB transposition-based immunotherapy, we employed high throughput sequencing (Illumina) and profiling (BlueBioU supercomputer) of the SB insertion sites in T cells. Our SB clinical vector inserted 99.999% of the time at expected TA dinucleotide sites, with 44% of the insertions localizing to intragenic loci and the remainder 56% intergenic. The vast majority (96.5%) of intragenic insertions are intronic while the majority (>60%) of intergenic transpositions fall within non-coding repeat regions. By linking microarray gene expression profile to the vector insertion profile, we find that the number of transcriptional start sites (TSS) hit is proportional to the expected ‘open’ conformational loci for the starting population of quiescent T cells. Compared to immunotherapy infusing T cells genetically modified with retrovirus, the integration profiles for SB-modified T cells are favored as: 1) there are more insertions within intergenic regions (56% SB vs. 44% in retroviral), 2) insertions concentrated at TA sites which have a different genomic distribution profile than retroviral insertion sites, 3) TSS associated with quiescent T cells were favored reflecting the electro-transfer of SB DNA plasmids into non-proliferating T cells vs. retroviral protocols that require transduction of activated T cells. Scanning for potential danger loci (e.g. oncogene, tumor suppressor, miRNA etc.), SB integration profiles compare favorably with retroviral insertions. In addition, we identified potential “safe harbor” genetic loci for future targeted modifications. Opportunities in immunotherapy and other personalized medicine modalities will be fully realized when the actual and perceived risks are understood and perhaps mitigated. In the absence of targeted insertions by clinical vectors, the next best option is random integration with an evenly distributed insertion profile across the whole genome to minimize hot spot and clonal expansion of therapeutic T cells. We now seek to proactively profile the T-cell products prior to infusion and follow up sampling to help clinicians in data-driven decision making in a time-sensitive manner. Our methods and findings are consistent with the human application of SB system and the harnessing high throughput supercomputing resources to help clinicians mitigate potential risks. Disclosures:No relevant conflicts of interest to declare.

Immunotherapy opportunities in ovarian cancer

Ovarian cancer is responsible for the majority of gynecologic cancer deaths and despite the highest standard of multimodality therapy with surgery and cytotoxic chemotherapy, long-term survival remains low. With compelling evidence that epithelial ovarian cancer is an immunogenic tumor capable of stimulating an antitumor immune response, renewed efforts to develop immune therapies to augment the efficacy of traditional therapies are underway. Current immunotherapies focus on varied modes of antitumor vaccine development, particularly with the use of dendritic cell vaccines, effective methods for adoptive T-cell transfer and combinatorial approaches with immune modulatory therapy subverting natural tolerance mechanisms or boosting effector mechanisms. Additional combinatorial approaches include the use of cytokines and/or chemotherapy with immune therapy.

A Second Prophylactic MHC-Mismatched Bone Marrow Transplantation Protects Against Rat Acute Myeloid Leukemia (BNML) Without Lethal Graft-Versus-Host Disease

We have employed a rat model for human acute myeloid leukemia, a promyelocytic leukemia in the BN rat strain (BNML), to develop new protocols for immunotherapy in combination with allogeneic bone marrow transplantation (alloBMT). The status of mixed chimerism in allotransplanted rats provided an opportunity for immunotherapy using alloreactive donor cells. In addition to T or natural killer (NK) cells, we introduced a second infusion of bone marrow cells as prophylactic donor lymphocyte infusions (DLI) to test whether an effective graft-versus-leukemia (GVL) response could be obtained without clinical graft-versus-host disease (GVHD). BN rats were sublethally irradiated and transplanted with T-cell depleted bone marrow cells from either fully major histocompatibility complex (MHC)-mismatched (PVG) donor rats or MHC-matched (PVG.1N) as controls. Seven days after transplantation, rats were given 500 leukemic cells to mimic minimal residual disease. Additional cellular therapy was given at day +7. The efficiency of DLI was monitored by chimerism analysis in peripheral blood. Rats receiving infusions of NK cells succumbed to leukemia. T-DLI induced complete donor T-cell chimerism and lethal GVHD. A second alloBMT protected against leukemia. This effect was dependent on an MHC incompatibility between the donor and host and also on the presence of alloreactive T cells in the second bone marrow inoculum, resulting in an increased, mixed donor T-cell chimerism. A second prophylactic transplantation influenced the degree of T-cell chimerism to balance favorably between GVL and GVHD. If applicable to humans, repeated alloBMT may provide a novel approach to leukemia therapy.

Translation of cancer immunotherapies

In response to our commentary defining potential barriers to development of novel immunotherapy opportunities, Skipper and colleagues describe a unique cancer immunotherapy consortium developed by the Ludwig Institute for Cancer Research (LICR) and joined by the Cancer Research Institute (CRI). The LICR-CRI cancer vaccine collaborative (CVC) funds units in roughly 20 institutions. These units participate in a set of coordinated cancer vaccine clinical trials focused on vaccination with a limited number of tumor antigens identified at LICR and evaluates both the generation of antigen-specific immune responses as well as clinical outcomes. As director of both institutes, Dr. Old has marshaled their vast collective resources in a visionary manner to create a multi-institutional mini-Manhattan Project. CVC's funding base allows the organization to circumvent some of the regulatory and 'public-private partnership' barriers outlined in our commentary. However, the LICR-CRI CVC is arguably so unique, it represents the exception that proves the rule.