Toward the next waves of cancer immunotherapy: 11th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 14–16, 2013
KeywordsCIMT 2013 Cancer immunotherapy Meeting report Targeted therapies
With a record number of 760 international participants, 78 speakers and 264 abstracts, the 11th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) launched into its second decade. Recent breakthroughs in the clinic were reached for immune-modulatory antibodies (e.g., ipilimumab), dendritic cell (DC)-based vaccines (e.g., Provenge) and adoptive transfer of immune-receptor-engineered lymphocytes [e.g., CD19 chimeric antigen receptors (CARs)]. Despite the first success stories in the field, observed clinical responses are currently either mostly moderate or restricted to a fraction of patients or tumor entities. Consequently, the slogan for CIMT 2013 was ‘Advancing Targeted Therapies’ to the next level. Advances in the field to improve the success rates of immunotherapy were discussed within the community in sessions on cellular therapies, improving immunity, immunoguiding, combination therapy, tumor environment and tumor vaccination. The enthusiastically discussed highlights and trends during the meeting are reviewed in the following meeting report. These are exciting times for the CIMT community and for the whole field of CIMT.
Immune checkpoint inhibitors and combinations thereof
FDA’s approval of the anti-CTLA-4 antibody ipilimumab in March 2011 for treatment of late-stage melanoma patients has been a milestone for oncoimmunology. As the medical lead in immunology/oncology at Bristol-Myers Squibb at that time, Axel Hoos (now at Glaxo Smith Kline Pharmaceuticals, Collegeville, USA) was one of the key persons responsible for the development of ipilimumab in melanoma and other indications. He explained that ipilimumab was a pioneering agent that stimulated the development of a whole class of immune-modulatory antibodies that now includes an increasing number of agents (e.g., anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-OX-40) developed by various commercial sponsors (e.g., BMS, Merck, Curetech, Amplimmune, GSK, and Genentech). Axel Hoos hypothesized that ipilimumab as well as other new antibodies and small molecule inhibitors applied as monotherapy may hold a high therapeutic potential but that combination therapies hold even greater promises in the future. Here, ‘vertical’ combinations target molecules within the same pathway (e.g., Dabrafenib and Trametinib targeting BRAF and MEK, respectively, within the MAPK pathway), whereas ‘horizontal’ combinations inhibit targets across pathways. These as well as other immunotherapy combinations are being explored. Since combination therapy is becoming an important treatment modality for cancer and other complex diseases or conditions, the EMA and FDA have recently published guidelines for the co-development of two or more novel (not previously marketed) agents for use in combination (EMA: Guideline on the evaluation of anti-cancer medicinal products in man (EMA/CHMP/205/95/Rev.4); FDA: Co-development of Two or More New Investigational Drugs for Use in Combination). In particular, according to those guidelines, co-developing investigational drugs should be considered (1) if the combination has a compelling biological rationale, (2) if preclinical data or short-term clinical studies suggest that the combination provides additive or synergistic activity or a more durable response compared with the corresponding monotherapies or (3) if there are compelling reasons that these agents cannot be developed individually (e.g., due to rapid development of resistance to monotherapy and/or limited activity of the agents when used as monotherapy). With respect to immunotherapies, Axel Hoos stressed that their unique clinical effects should be acknowledged during clinical development. Tumor growth kinetics and progression characteristics can potentially reflect the interplay between the immune system and the tumor explaining why treatment beyond progression needs to be considered A methodological framework is now available to support clinical development of immunotherapies, consisting of assessment of anti-tumor responses by new immune-related response criteria and modified clinical trial designs. Also conventional clinical trial endpoints, such as progression-free survival, do not always appropriately consider the biological effects of immunotherapeutics. There is an urgent need for the development of reliable biomarkers that can reproducibly determine whether an immune intervention achieved its biological effect and can predict responses to a given treatment and clinical outcomes.
Ira Mellman (Genentech, San Francisco, USA) described the current landscape of immunotherapeutic strategies as the third wave of cancer therapy following a first wave of conventional and a second wave of targeted approaches. He presented new data on a PD-L1-blocking antibody, which has been designed to overcome tumor-induced T-cell suppression and is currently in clinical validation. PD-L1, which is broadly expressed on human cancers, renders T cells unresponsive or ‘exhausted’ by binding to PD-1 that is predominantly expressed by activated T cells. Since PD-L1 is also expressed on effector and memory T cells, the Fc region of this antibody was modified to eliminate the ability to confer antibody-dependent cell-mediated cytotoxicity. Like ipilimumab, anti-PD-L1 appears to be an attractive option for combinations. In this context, it will be critical to understand the potential interference of different targeted or chemotherapeutic agents with immune-therapeutics in detail. For example, in preclinical colorectal tumor models the activity of anti-PD-L1 was enhanced when combined with oxaliplatin or carboplatin, but reduced when used in combination with docetaxel or temozolomide. Another combination that makes biological sense is the co-administration of anti-CTLA-4 and anti-PD-L1 antibodies. Both agents counteract T-cell immunosuppression at distinct stages. Physiologically, CTLA-4 is upregulated early during T-cell activation and blocks further T-cell stimulation. Blockade of CTLA-4 can thus support induction of de novo T-cell responses and enhance pre-existing responses. By contrast, anti-PD-L1 antibodies restore the activity of exhausted T cells. First promising results of this combination have been presented at the ASCO2013 meeting (Abstract #9012, Jedd D. Wolchok).
The combinations of checkpoint inhibitors were addressed in greater detail by Ramy Ibrahim (MedImmune, Gaithersburg, USA). He reviewed a number of recently conducted preclinical and clinical studies combining ipilimumab with tumor vaccines, other immunemodulating, anti-angiogenic, chemotherapeutic or targeted agents. Any combination of investigational agents should take into account the potent ability of CTLA-4 blockade to activate the immune system. This is associated with a significant incidence of inflammatory toxicities, which generally can be readily managed with medical treatment. Trials of new combination therapies should therefore be conducted carefully, even if the individual agents have regulatory approval and distinct mechanisms of action, as intensified anti-tumor effects may be associated with increased likelihood or severity of these side effects. In light of this, Ramy Ibrahim raised the following questions that need to be answered for each novel combination being administered to patients: (1) What preliminary data is needed before starting combination treatments? (2) What conclusions can be drawn from potential toxicities and what are the mechanisms of these toxicities? (3) How informative are preclinical data? and (4) What would be the optimal dose, sequence and timing of the combination therapy? Ramy Ibrahim stated that having these questions in mind Medimmune and AstraZeneca are now about to explore various regimens combining immune modulators with small molecule inhibitors or chemotherapy. Molecular targeted or chemotherapeutic drugs that lead to immunogenic cell death may offer great promise for boosting anti-tumor responses in combination with treatment designs with immunologically active agents. However, small molecule inhibitors or cytotoxic chemotherapy can also antagonize the development of anti-tumor immunity by inhibiting DC or T-cell function or by modifying the tumor or its microenvironment. Careful consideration regarding dose, sequence and timing of the combination regimen can help to identify conditions where these drugs act in an immunostimulatory way.
In summary, many academic and commercial entities are now studying concepts that combine related—as well as unrelated—agents in various settings. The field has learned to acknowledge the peculiarities of immunotherapies and to ask the right questions that will allow rational design of combination therapies and their safe and effective development in patients. It seems inevitable that new combination therapies will soon change clinical practice in oncology.
Gene and cell therapy
Autologous CD19-targeted CAR-modified T cells have been demonstrated to show extraordinary anti-tumoral efficacy in patients with advanced leukemia as published in landmark proof-of-concept studies by the groups of Carl June and Michael Kalos [University of Pennsylvania, Pennsylvania, USA (UPenn)], Renier Brentjens [Memorial Sloan Kettering Cancer Center (MSKCC)] and Steven Rosenberg and James Kochenderfer [National Cancer Institute (NCI)]. Michael Kalos reported on a current trial targeting refractory and relapsed CD19 + B cell malignancies in adults [chronic lymphocytic leukemia (CLL)] and children [pediatric acute lymphoblastic leukemia (pALL)], with second-generation CARs that were engineered with 4-1BB domains to confer additional co-stimulatory signaling. The therapy resulted in a strong clinical response in ten of 14 CLL patients and two of two pediatric ALL patients, respectively. Both children had a remission of their leukemia, accompanied by the robust expansion of the transferred CTL019 cells in vivo, with CTL019 cells detected in bone marrow and the cerebrospinal fluid. The potent anti-leukemic effects were associated with robust expansion and long-term persistence of CTL019 cells. Patients with heavy tumor burden showed delayed tumor lysis syndrome and cytokine release syndrome. However, one child, previously treated and relapsed after allogeneic cord-blood transplantation and blinatumomab therapy, relapsed after CTL019 therapy highlighting the need to develop additional CAR targets for ALL. Renier Brentjens (MSKCC, New York, USA) summarized the results of published clinical trials conducted at MSKCC, NCI and UPenn, where patients with CLL and other leukemias were treated with second-generation CARs targeting CD19. However, conclusions are still limited by the rather small patient numbers and inter-trial variability. To overcome this problem, MSKCC, UPenn and CHOP founded a multi-center consortium aiming to harmonize procedures and address variables in gene transfer and CAR design.
In order for CAR T cells to target tumors with a hostile microenvironment (e.g., solid tumors), functionally enhanced T cells may be needed. Renier Brentjens introduced the so-called ‘armored’ or fourth-generation CARs, which are genetically modified to express cytokines or co-stimulatory molecules. In mouse models, CAR-engineered T cells, additionally modified to produce IL-12, showed improved tumor eradication. IL-12 was shown to render T cells refractory to regulatory T cell) mediated inhibition. Other mechanisms of action partially contributing to the effect may be activation of NK cells and reversion of anergy in tumor-infiltrating lymphocytes.
Also with regard to ‘armored’ CAR development, Laurence Cooper (University of Texas, Houston, USA) presented mouse data suggesting that co-expression of membrane-bound IL-15, which leads to auto- or trans-stimulation of CAR T cells, may improve anti-tumor efficacy and in vivo persistence of CAR-engineered T cells. Furthermore, he reported on a method of DNA plasmid-based CAR T-cell engineering that represents an inexpensive and nimble alternative to viral gene transfer, which has reached clinical stage. Using the Sleeping Beauty transposon/transposase system and a protocol of ex vivo expansion of CAR T cells with artificial antigen-presenting cells and cytokines (IL-2, IL-21), he and colleagues efficiently engineered T cells to express a second-generation CAR directed against CD19. Another way to improve the adoptive T-cell transfer protocols other than optimizing the lead structure of the immune receptor or the vector for gene transfer is to improve quality of the T cells themselves. In order to do that, it is desirable to polarize T cells toward a phenotype with superior anti-cancer activity. According to the findings of Luca Gattinoni (National Cancer Institute, Bethesda, USA) and his group, the differentiation state of CD8+ T cells critically determines the effectiveness of anti-tumor therapy. Less differentiated T cells with stem cell-like properties possess enhanced capacities to engraft, persist and mediate prolonged anti-tumor immune response, in contrast to the rather short-lived differentiated, cytotoxic CD8+ T cell phenotype. They observed that the latter was associated with specific metabolic features, such as reduced mitochondrial fatty acid oxidation and enhanced glycolysis as compared with the stem cell-like phenotype. Notably, constitutive activation of glycolytic flux in T cells by over-expression of phosphoglycerate mutase limited memory T-cell formation in vivo. This suggests that metabolic re-programming by inhibition of glycolysis in T cells can be employed to enhance long-term T-cell survival and function. The proof of concept was shown in a mouse tumor model, where the glycolysis inhibitor 2-deoxy glucose improved memory T-cell formation, anti-tumor effects and survival.
Further, conceivable improvements to the cell carriers that may be reached in the future and that may open the door for off-the-shelf therapy with CAR-engineered lymphocytes were presented by Laurence Cooper. The concept of an off-the-shelf cellular therapy is based on manufacturing of CAR-engineered T cells from various sources of blood including umbilical cord blood, an important transplant source for recipients with uncommon tissue types. Utilizing the Sleeping Beauty transposon/transposase system for transfer of engineered zinc-finger nucleases, both HLA and the T-cell receptor from a healthy donor cell may be eliminated while introducing the CAR to the same T cell. This would result in allogeneic CAR T cells, which can be delivered to a given recipient off-the-shelf, making cell therapy easier and cheaper while opening broader applications of this technology.
The incredible effects achieved utilizing CAR T cells targeting leukemia have stimulated fast progress and led to consortia that now systematically introduce and compare new components that are designed to increase therapeutic success rates. The increased understanding on lead structures, vectors for gene transfer and cellular carriers allow further rational advances of these therapeutic approaches. It has become clear that the use of adoptive T-cell transfer as a new therapeutic modality to treat cancer is here to stay.
Sipuleucel-T (Provenge) was the first clinically approved cellular immunotherapy to demonstrate prolongation of the survival of patients suffering from advanced to late-stage hormone-refractory prostate cancer. The FDA approval in 2010 was a cornerstone for cellular immunotherapy. Approval of more and improved tumor vaccination strategies are highly anticipated by the field.
Zaima Mazorra-Herrera (Center of Molecular Immunology, Havana, Cuba) presented clinical data of a regimen combining the anti-idiotypic antibody racotumomab and the epidermal growth factor (EGF)-based protein vaccine CIMAvax EGF for treatment of advanced non-small cell lung cancer (NSCLC) patients. The safety and clinical effects of both agents as monotherapies were studied in large clinical studies leading to the approval of racotumomab in Argentina and Cuba, and CIMAvax EGF in Cuba and Peru for the treatment of advanced NSCLC.
Racotumomab is an anti-idiotypic antibody that mimics Neu glycolyl (NGc)-GM3 containing ganglioside. It elicits humoral immune response against NGcGM3–ganglioside, which is present on the surface of various solid tumors of NSCLC but usually not detected in healthy tissues. Early clinical studies suggested high immunogenicity and low toxicity of this vaccine formulation. CIMAvax EGF is a vaccine consisting of recombinant human EGF chemically conjugated to recombinant Neisseria meningitides P64 k protein and mixed with Montanide ISA 51 adjuvant. This preparation renders the ligand EGF immunogenic and potently induces the release of effector antibodies against EGF in vaccinated patients. Clinical trials confirmed that low-dose cyclophosphamide treatment 72 h before the first immunization could enhance the immunogenicity of CIMAvax EGF. An immune response against autologous EGF was induced in patients with different advanced stage tumors.
The favorable toxicity profiles and the complementary modes of achieving tumor control raised the hypothesis that further improvement of treatment outcome could be achieved through combination of racotumomab and CIMAvax EGF. The preliminary data of the combination regime look promising: Improved antibody response against EGF and Racotumomab were achieved and 30 % of treated patients were alive at 18 months after the inclusion. These findings suggest a benefit for first-line chemotherapy progressors in NSCLC. In order to confirm these results, a new randomized clinical trial in advanced NSCLC patients unfit for chemotherapy will be performed. The two presented vaccines and their combination raise questions reaching beyond the biological base for their synergistic activity. To what extent the large amount of data from clinical trials, mainly conducted outside of European and US regulatory frameworks, can be considered when seeking EMA and FDA approval?
Karl-Josef Kallen (CureVac GmbH, Tübingen, Germany) introduced the RNActive vaccine platform. An RNActive vaccine is a mix of two RNA components: one free-engineered RNA that utilizes the antigen expression and one protamine-complexed RNA to induce an adjuvant effect. For therapy, the RNA mix is injected intradermally without any transfection agent or further adjuvant. The vaccine induces CD8 + and CD4 + T-cell responses and generates immune memory as shown in preclinical tumor challenge experiments. The combination with anti-CTLA-4 antibodies results in a synergistic effect and induces antigen spreading in preclinical experiments. The technology is currently being evaluated in different clinical studies. In a phase I/IIa study to treat castration resistant prostate cancer, with rising PSA it was shown that the vaccine CV9103, coding for four antigens (PSA, PSCA, PSMA and STEAP) is highly immunogenic and induces strong T-cell responses. In most cases (58 %, n = 26) more than one immune response could be elicited. Vaccination resulted in a favorable median overall survival when compared with historical data from other immunotherapies. These encouraging results led to a currently ongoing double blind, placebo-controlled phase I/IIB trial with the related vaccine CV9104 utilizing the same antigens, with the aim to achieve a prolonged overall survival.
Hans-Georg Rammensee (University of Tübingen, Tübingen, Germany) shared his vision to exploit mutated tumor antigens for personalized vaccine approaches. In contrast to differentiation antigens or over-expressed self-antigens, tumor mutations may give raise to true neo-antigens for which T cells that have left the thymus should not be tolerant and express high affinity TCRs. This strategy for individualized therapy that is currently pursued in Tübingen is designed as a two-step approach. First, patients are vaccinated with off-the-shelf peptides targeting shared tumor-associated antigens and chosen according to the patients’ HLA alleles. These trials of the off-the-shelf approach utilizing HLA-A2 and HLA-A3 cocktails to target renal cell carcinoma were initiated last year. Second, subsequent vaccination is performed with mutated peptides that are selected and manufactured on demand following tumor mutation analysis by next generation sequencing and prediction of mutation-derived HLA ligands. So far, a single patient has received a peptide vaccine targeting three patient-specific tumor mutations. In this single case, however, the induction of mutation-specific T cells was not achieved. More patients need to be treated to reach a clinical proof of concept for this approach. A similar two-step concept for the treatment of glioblastoma will also be executed in the near future by an EU consortium jointly led by immatics biotechnologies GmbH and BioNTech AG in the Glioma Actively Personalized Vaccine Consortium (GAPVAC).
The success of the new strategies targeting such patient-specific mutations will heavily depend on the mutation discovery and target mutation selection process. The retrospective analysis to prove immunogenic potential of a given selected mutation is challenging and results in an increased complexity in immunomonitoring. One step on the way to personalized immunomonitoring was presented by Marit van Buuren (Netherlands Cancer Institute, Amsterdam, the Netherlands). Tumor regression after treatment with ipilimumab is thought to be at least in part mediated by antigen-specific T cells. So far, it has not been analyzed, which exact T-cell specificities are involved in ipilimumab-induced cancer regression. To answer this question, Marit van Buuren and her team analyzed the neo-antigen-specific T-cell repertoire in nodular melanoma after initial treatment with ipilimumab. T-cell reactivity against non-mutated tumor-associated self-antigens has been shown to induce only modest T-cell responses. A potential involvement of mutated neo-epitopes in T-cell control would fit well with the observation that the mutation load in sun-exposed melanomas is particularly high. An exome-guided analysis of T-cell reactivity in one patient revealed reactivity against two neo-antigens. One is a mutated epitope of the ATR (Ataxia Telangiectasia and Rad3 related), where a dominant T-cell response was detected that increased fivefold after Ipilimumab treatment. These data provide the first demonstration of cancer exome-guided analysis to dissect the effects of melanoma immunotherapy and will help to improve the development of mutation-based tumor vaccines.
Personalized vaccine approaches targeting tumor-specific mutations have been a focus of CIMT for the last couple of years. This year’s follow-up on the topic showed that further gradual advances were reached. First proof-of-concept clinical studies with mutanome-based vaccines are soon to be initiated.
The tumor microenvironment plays a critical role for both tumor progression and tumor control by the immune system. In particular, the nature of the tumor immune microenvironment has been shown to influence disease outcome. It is becoming more and more evident that novel therapeutic approaches for tipping the balance of immune responses from tumor protection toward tumor rejection will be essential for an effective CIMT.
As recapitulated by Antonio Mantovani (Instituto Clinico Humanitas, Milan, Italy), cancer-related inflammation is characterized by recruitment of cells of the monocyte–macrophage lineage to tumor tissues. M1 macrophages contribute to the T-cell-mediated elimination and equilibrium phases, whereas tumor progression has been associated with a phenotypic switch from M1 to M2 macrophages. Hence, tumor-associated macrophages are an attractive target for anti-tumor therapies. Antonio Mantovani showed that the chemotherapeutic agent trabectedin is preferentially toxic for cells of the monocyte–macrophage lineage, activating caspase-8-dependent apoptosis in these cells. The subsequent depletion of tumor-associated macrophages in vivo is sufficient to induce an anti-tumoral activity in mouse tumor models, suggesting that trabectedin may exert favorable effects on the tumor microenvironment. Clinical trials are underway to test trabectedin in soft-tissue sarcoma patients. Another strategy to modulate the tumor microenvironment toward the M1 phenotype was presented by Vincenzo Bronte (Verona University Hospital, Verona, Italy). In his lecture, he talked about the control of tumor-induced immune-regulatory networks by microRNAs (miRNAs). He explained that using miRNAs they targeted the tumor-infiltrating myeloid (CD11b+) cells in an attempt to reduce the number of precursor suppressive cells. Enforced expression of miRNA142-3p reduced the number of suppressive macrophages with an M2 phenotype. This effect was shown to be dependent on the modulation of both the IL-6 receptor signaling and the transcription factor C/EBPβ. Hence, miRNA142-3p modulation could be an efficient tool in tumor therapy and in future its therapeutic use may be possible with the aid of nanoparticles and dendrimers.
A further method of targeting the tumor microenvironment was outlined by George Prendergast (Lankenau Institute for Medical Research, Wynnewood, USA). He explained that indoleamine 2,3-dioxygenase (IDO) can help to drive immune escape in a number of ways. IDO-mediated tryptophan depletion leads, among other things, to an immunosuppressive tumor environment by amplifying tolerogenic antigen-presenting cells, expanding regulatory T cells, and decreasing effector T-cell levels. This makes IDO a great target for cancer therapy.
In summary, the important role of the tumor microenvironment is increasingly being acknowledged and there is an improved understanding of the cellular and molecular mechanisms of tumor protection. Novel knowledge generated over the last few years now fuel the hope that new strategies to interfere with the microenvironment, to better control tumor growth, can be rationally developed.
Cutting edge technology was presented by John Bell (Ottawa Hospital Research Institute, Ottawa, Canada). He showed data demonstrating that immune evasion could be counteracted by combining the abilities of oncolytic viruses to act as cancer vaccine carriers and at the same time to influence the tumors micromilieu. Oncolytic viruses have become a promising therapy approach and a prime example of how to exploit several aspects of cancer physiology to induce a cancer-selective and multi-modal response. Even without engineering, viruses have intrinsic cancer selectivity, as some major characteristics of malignant cells promote viral growth. Anti-viral mechanisms like apoptosis, cell cycle arrest, immune activation and inhibition of vessel formation are usually not fully functional in cancer cells. After successful infection, viruses are self-amplifying and spread within and between tumor cells. In doing so, they attack the tumors in multiple ways rather than addressing single targets: Besides lysis of infected cells and destruction of vasculature, immune activation is an important mechanism of action. Accordingly, John Bell showed evidence that with oncolytic viruses, syngeneic tumors could be eradicated in immunocompetent mice better than in immunodeficient animals and that immunological memory had been established after viral treatment. The engineered oncolytic pox virus JX-594 (with deletion of the viral thymidine kinase gene to enhance cancer specificity and addition of the GM-CSF gene) showed promising results in early human trials, with some cases of long-term survival of HCC, RCC and melanoma patients. Long-term effects were found to be associated with a humoral immune response. The immune-activating potential can be further enhanced by engineering viruses to express relevant tumor antigens. Mouse data demonstrate that this concept of an ‘oncolytic vaccine’ works best when priming and boosting occur with different viruses. For boosting, a maraba virus-based platform appeared most potent as compared with other viruses, leading to a large increase in tumor-infiltrating lymphocytes and antigen spread to different cancer antigens. Intravenous administration was superior to intranodal and intramuscular administration routes with respect to T-cell response, and systemic targeting also promises enhanced efficacy against metastatic disease. A clinical trial is now planned for Maraba virus expressing MAGE-A3. In cynomolgus macaques, Maraba virus was acceptably safe and showed evidence of moderate T-cell response induction.
With the recent report on Amgen’s TVEC meeting, its primary endpoint in a phase III trial, and the increasing understanding of the non-immunological and immunological factors contributing to the anti-tumoral effects of oncolytic viruses, the expectations from clinical investigators have clearly been raised over the last years. The outlook for oncolytic viruses as novel therapeutics to treat cancer is positive.
Over the last 8 years, CIMT has hosted working groups focused on specific topics. During the annual meeting, the working groups provide updates on their activities and organize sessions to address burning questions in their respective area. Next to the two established groups—CIMT Immunoguiding Program (CIP) and the CIMT Regulatory Research group—a novel group has been introduced this year, namely CIMT Endeavour.
Sjoerd van der Burg (LUMC; Leiden, the Netherlands) provided an update on the activities of CIP. The group has continued to organize proficiency panels for commonly used T-cell assays, such as the ELISPOT assay and a comparison of different protocols for in vitro stimulation of peripheral blood mononuclear cells. The group is about to initiate new proficiency panels for the first time addressing flow panels to analyze myeloid-derived suppressor cells. CIP, together with the CIMT Consortium of the Cancer Research Institute have joined forces with Immudex (Copenhagen, Denmark) to outsource part of the proficiency panel activities to a service provider. The aim of this activity is to offer an affordable service of external quality control and benchmarking of immune assay performance to the scientific community at a regular base. CIP has been studying formulations for long-term storage of HLA-peptide multimers and made progress in two research projects on automated analysis of flow data and the generation of reference samples for the control of immune assay performance. Last but not least, CIP is supporting the implementation phase of the MIATA project to achieve transparent reporting on results from T-cell assays.
Ulrich Kalinke (TwinCore, Hanover, Germany) provided an update on the activities of the Regulatory Research group, which had been commenting on several draft guidance documents from both EMA and FDA during public consultation periods throughout the last 4 years. Following up on the guidance documents that were finally published, the group was happy to see that some of the comments made during public consultation were implemented by the agencies. Topics discussed during the scientific session included the regulators’ expectations on laboratories performing analyses within clinical trials and the differences of developing companion diagnostics between Europe and the United States.
CIMT Endeavour is a new working group focusing on the translation and commercialization of cancer immunotherapies and diagnostics. They organized a workshop where company founders and experts discussed funding, initiatives, viable business models and product development. Challenges that European biotech companies face in early-, middle- and late-stage development were discussed between biotech representatives and experts from pharmaceutical and investment companies. The workshop made clear that it takes a lot of time, expertise and money to translate new potential-bearing technology up to the point where it may become an approved treatment for patients. It is clear that on top of excellent science and new technologies, sustainable business models and managerial skills are needed to develop new therapies for patients. Most importantly, many scientists still lack fundamental knowledge regarding which factors drive commercialization, even though they should be taken into account during the early stages of preclinical and clinical research activities. CIMT Endeavour will continue to systematically address this topic, enabling interested members of the CIMT community to better understand how to commercialize science for the benefit of patients.
After the clinical breakthroughs for checkpoint inhibitors, a first therapeutic vaccine and cell therapeutics reported in the last years; novel developments are now emerging into the spotlight. The lectures presented at CIMT 2013 made it clear that researchers and investigators worldwide are rapidly advancing immune therapies that will inevitably lead to further groundbreaking clinical successes. It is not a matter of ‘if’ but rather ‘when’ new immunotherapies to treat cancer will become available for patients, in these exciting times for the field of CIMT. The 12th CIMT Annual Meeting will be held on May 6–8, 2014.
The authors would like to thank Dr. Stephen Reece (Mainz, Germany) for carefully proofreading the meeting report. Ute E. Burkhardt acknowledges support from the German Research Foundation (BU 3028/1-1). Selected sessions of the CIMT meeting were made possible due to research grants from the German Bundesministerium für Bildung and Forschung (BMBF grant: 031A018) and the Deutsche Forschungsgemeinschaft (DFG grant: GZ: HU 852/4-1; AOBJ: 602849). The CIMT-working group CIP receives support for educational activities by the Wallace Coulter Foundation (Florida, USA).
Conflict of interest
The authors declare that they have no conflict of interest. Cedrik M. Britten has been co-organizer of the meeting. Björn-Philipp Kloke has been co-organizer of the CIMT Endeavour workshop.