8th Annual Canadian Cancer Immunotherapy Consortium (CCIC) Symposium 2015—May 20–22, Vancouver, Canada

From May 20–22, 2015, Canadian and international scientists held an intense meeting in beautiful Vancouver, British Columbia, focused on immunotherapy of cancer. This year’s 8th CCIC meeting brought novel innovations from both academia and industry, broadly extended our understanding of large data analysis, targeted cell and antibody therapeutics and identified new challenges for the successful deployment of cancer immunotherapeutics. The collection of world-class scientists and the highly social meeting structure afforded an excellent opportunity for networking and discussing data. Many of the 14 speakers presented their ongoing basic and clinical studies in the context of historical data from their own and pioneering laboratories. The meeting was an outstanding reminder of the progress in the field of cancer immunotherapy, speaking to past successes and failures, current ambitions and future potential. Alone and in combination with additional interventions, immunotherapeutics are showing great promise for the treatment of patients with cancer. Here, we summarize work presented by the speakers, highlighting technological and conceptual advances and contextualizing them in the field of cancer immunotherapy. Current efforts, ongoing innovations and perspectives are discussed.

Adoptive cellular therapy strategies: successes and opportunities

The ability of the immune system to detect and control cancer is well recognized; in particular, CD8⁺ cell infiltration in the tumor correlates with improved prognosis. These observations have inspired the development of adoptive cell therapies (ACT) that enhance cytotoxic anti-tumor activity. Two modified T cell types form the basis of current ACT approaches: tumor-infiltrating lymphocytes (TIL) and chimeric antigen receptor (CAR) T cells. The goal of both strategies is to promote the activity of anti-tumor cytolytic T cells to target and destroy tumor cells. Challenging the success of ACT is low persistence and proliferation of the transferred cells in vivo, difficulties in identifying ideal target antigens, MHC restriction and tumor-mediated immune escape mechanisms. These elements are now the focus of careful engineering in next-generation strategies to improve ACT efficacy. Clinical ACT trials using novel strategies are underway, and the ongoing challenges and successes were discussed at the CCIC.

Tumor-infiltrating lymphocytes therapy

TIL are a rich source of tumor antigen-specific T cells that can be harvested from biopsies and surgical tumor resections, expanded ex vivo and infused back into the patient for directed anti-tumor activity. An advantage of this therapy is that TIL are autologous and therefore restricted to the patient’s HLA. Furthermore, TIL are polyclonal and responsive to many different epitopes in a given tumor, making outgrowth of escape mutants less likely compared with monotargeted therapy and eliminating the challenge of identifying antigenic epitopes. A single preparation of autologous TIL can be cryopreserved and used for ongoing therapy; however, consistent harvesting and production of patient-specific TIL have stalled the widespread use of this technology. To date, the application of TIL therapies has been limited to academic institutions, making them highly inaccessible to the average patient. Lazlo Radvanyi of the Lee Moffitt Cancer Center (Tampa, USA) and Chief Scientific Officer of Lion Biotechnologies (New York, USA) described the first TIL manufacturing outside of an academic center. Lion Biotechnologies has developed a platform to centralize TIL expansion: The clinician sends the tumor sample to Lion Biotechnologies where TIL are isolated, expanded and ultimately returned to the hospital for infusion into the patient. Importantly, this advance makes TIL therapy and research feasible to patients and practitioners outside of major academic institutions.

TIL therapy has been most successful in the treatment of melanoma; in other tumor types, however, TIL therapies have been less effective. TIL are a highly heterogeneous cell population containing many types of lymphocytes, the minority of which are functional tumor-specific effector T cells. In an effort to improve TIL therapy against metastatic gastrointestinal (GI) tract cancers, Eric Tran from Steven Rosenberg’s laboratory at the National Cancer Institute (Bethesda, USA) discussed an approach to select T cell populations directed against the specific mutations in a given tumor. To identify mutation-reactive T cells, TIL are harvested from surgically resected GI tumors, expanded ex vivo and then screened against autologous antigen-presenting cells transfected with minigene constructs encoding the mutations expressed by the patient’s tumor. Using this approach, mutation-reactive T cells could be detected in virtually all patients with metastatic GI cancers. By expanding mutation-specific T cells, it is possible to intelligently direct personalized anti-tumor ACT. In a previously reported patient with metastatic bile duct cancer, tumor regression ongoing at 16 months was observed after treatment with a highly enriched population of mutation-reactive CD4⁺ T cells. However, three additional patients treated with mutation-reactive CD8⁺ T cells had progressive disease, which prompts further consideration of the dose, characteristics and clonality of T cells that would best eliminate tumor cells and overcome the suppressive nature of the tumor microenvironment. Some of these factors could potentially be overcome by using a personalized TCR gene therapy approach.

Given their prior exposure to the suppressive tumor microenvironment, additional interventions and stimulation may be required to rescue TIL from anergy and promote cytotoxicity. Radvanyi described how Lion Biotechnologies is attempting to improve TIL function by genetically modifying the TIL population using lentiviral-mediated genetic engineering. To improve homing to the tumor, they have expressed CXCR2 on the TIL, as well as dominant-negative receptors to TGF-β or PD-1 in order to prevent inhibitory signaling. Further modifications to target inhibitors of T cell survival, activation and function include treatment of the cells with pharmacological compounds or targeting with CRISPR/Cas9. In vitro TIL expansion is further improved by use of artificial APCs and by identification and removal of suppressive TIL constituents such as CD3⁻CD56⁺ cells that inhibit CD3⁺ TIL expansion. Further supporting the need to subvert the active immunosuppression in the tumor microenvironment, speed poster presenter and first place poster winner Sarah Crome from Pamela Ohashi’s laboratory at the University Health Network in Toronto, Canada, demonstrated that a population of regulatory innate lymphoid cells (ILCs) with suppressive capacity are enriched in high-grade serous ovarian cancers and can inhibit the expansion and function of TIL.

Perhaps, the biggest challenge facing TIL therapy is the availability of effector cells. Not all patients have sufficient TIL to isolate from available tumor tissue, and the existing lymphocytes may not be functional or appropriately targeted to relevant antigens. In these cases, additional therapies, including those with engineered receptors, may be required for successful immunotherapy.

Chimeric antigen receptor T cell (CAR-T) therapy

The identification of relevant tumor antigens and neoantigens may foster directed and effective therapy against critical tumor components and the products of driver mutations. CAR-T cell approaches aim to modify a patient’s own effector T cells to recognize tumor-associated antigens. CAR-T cells can be developed from autologous, non-tumor derived T cells, and therefore, this technology does not rely on harvesting a sufficient number of cells or their preexisting antigen specificity. It does, however, rely on the ability to identify and target antigens of interest. A major challenge of CAR-T therapy is supporting their continued function against tumor cells. A suppressive tumor microenvironment and poor proliferation of adoptively transferred cells are major roadblocks to the successful application of cell-mediated therapeutics. Further, the tonic signaling established by the CAR and related co-stimulatory molecules could drive these therapeutic T cells into anergy. The success of adoptive cell therapies therefore likely requires interventions to secure the proliferation, activation and shielding of adoptively transferred cells.

Renier Brentjens, from Memorial Sloan Kettering Cancer Center (New York, USA), a founder of CAR-T technology, described its 17-year history including the successes and challenges faced in translating these therapies for clinical application. The first generation of CAR-T cells were engineered to express a fusion protein consisting of single-chain variable fragments (scFv) derived from monoclonal antibodies with known specificity to the intracellular domain of the CD3-ζ chain (molecule responsible for TCR signaling). While this provided proof-of-concept that T cells could be modified to express CAR, the T cells were insufficiently co-stimulated to trigger cytotoxicity and proliferation. Additional and complementary interventions added the intracellular domains of CD28 and other co-stimulatory molecules, including 4-1BB or OX40 to drive co-stimulation and, coordinately, better CAR-T cell proliferation and persistence in vivo. With that, these second- and third-generation CAR-T cell strategies have been associated with improved clinical success.

Cliona Rooney of the Baylor College of Medicine (Houston, USA) described her ongoing work using virus-specific T cells (VSTs) with CAR-T therapy in a keynote address. As hosts for CAR, VSTs accommodate CAR in highly competent effector memory T cells that can be triggered for proliferation by vaccination or reactivation of common latent viruses during tumor therapy including EBV, CMV, JC, AdV and VZV. The VST-based approaches rely on a preexposure to virus in order to have the appropriate precursor cells; however, these cells may be harvested from hematopoietic cell donors and/or haploidentical family members if they are not available in the patient. In particular, the use of VZV-specific T cells is generating encouraging results, where vaccines for primary and secondary infection open the possibility of expanding potent effector cell populations. In another keynote address, Philip Greenberg of the Fred Hutchinson Cancer Research Center (Seattle, USA) similarly endorsed VST as hosts for high-affinity, tumor antigen-specific T cell receptors (TCRs). After expressing WT-1 specific TCR in EBV-specific memory T cells, increased expansion and persistence of WT-1-specific T cells was observed in vivo in six patients with refractory and relapsing leukemia. In next-generation strategies to engineer T cell effector responses, Greenberg’s group is identifying high-affinity couples of α and β TCR chains and combining them to enhance the affinity of T cell-target interactions.

It is in the blood cancers—leukemia and lymphoma—that the best successes from CAR-T therapy have been reported. Both Rooney and Greenberg suggested that the myeloablation prior to hematopoietic cell transplantation in the treatment of these cancers may create a niche in which CAR-T cell proliferation would be supported. Whether this observation can be translated to support treatment of solid tumors was not discussed; however, partial myeloablation and/or the co-administration of pro-proliferative cytokines with adoptively transferred cells may boost the efficacy of this strategy.

Intelligent engineering strategies for ACT have made it possible to generate potent T cells targeting tumor-specific antigens. Their application in clinical trials, however, has met only modest success because the tumor microenvironment is actively immunosuppressive. Interfering with cytotoxic T cell function are regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), PD-L1 expression on tumor or immune cells and immunosuppressive cytokines (e.g., IL-10 and TGF-β). To overcome this hostile environment, Brentjens described novel interventions to create armored CAR-T cells. By engineering CAR-T cells for secretion of IL-12, natural killer (NK) and T cells are recruited for tumoricidal activity and pro-inflammatory cytokine production. Unlike previous interventions where IL-12 was systemically administered, production of IL-12 by CAR-T cells, which localize to the tumor microenvironment, is not associated with systemic toxicity. Therapeutic interventions that suppress Treg help to prevent and rescue effector T cells from anergy will be critical for the success of adoptive T cell approaches. In addition to armored CAR-T cells, combination therapies involving cyclophosphamide or checkpoint blockade are likely to meet this criteria. Whether elimination of Treg alone will be sufficient to support successful adoptive therapies remains to be determined. Hence, further improvement depends on a deeper understanding of the tumor microenvironment and identification of mechanisms to reverse immunosuppression.

The anticancer immune response and tumor microenvironment: challenges and opportunities

Tumor growth requires an overcoming of the intrinsic mechanisms aimed at maintaining homeostasis in vivo. A malignancy evolves this “fitness” by co-opting tolerogenic and immunosuppressive features normally used to control the immune response after pathogen clearance, prevent autoimmunity and facilitate healing and development (i.e., PD-1 and CTLA-4). Tumors that successfully develop and metastasize promote tolerance and actively suppress cytolytic activity by lymphocytes through direct antagonism of co-stimulation, by recruiting tolerogenic leukocyte subsets and conditioning the microenvironment with anti-inflammatory cytokines. Successful cancer immunotherapy therefore requires a reversal of immunosuppression to support the continued reactivity of native and adoptively transferred cytotoxic cells.

The immune microenvironment

The tumor microenvironment comprises a network of connected cellular compartments with complex interactions playing an essential role in the progression of disease. Keynote speaker Wolf Herman Fridman of INSERM (Paris, France) discussed the role of CD8⁺ T cell density and, more broadly, the distribution of effector cells and antigen-presenting cells (APCs) within the tumor as prognostic biomarkers. By extension, his findings imply that immune control of tumors can be predicted by the immune infiltration and organization within specific tumor types. He demonstrated that a local immune score can be assigned based on factors including the tumor stage and the number of tertiary lymphoid structures (TLS) present, with their composition indicating tumor prognosis and informing the optimal approach to treatment. Further refining the phenotype of TIL present in tumors may better predict outcome. Speed poster presenter and third place poster winner, Maartje Wouters from Hans Nijman’s laboratory at the University Medical Center Groningen (Groningen, The Netherlands), presented recent finding suggesting the presence of TIL with a more naïve phenotype (CD27⁺) may more broadly predict better outcome than the presence of CD8⁺ cells alone.

The prognostic effect of TIL can be variable in different types of cancer and sites of metastasis. Fridman described that in non-small cell lung cancer (NSCLC), a high density of CD8⁺ T cells, and in particular their localization to TLS, is associated with favorable outcomes. In clear cell renal cell carcinoma (ccRCC), where CD8⁺ T cells are less organized within the tumor microenvironment, a high density is associated with poorer prognosis. The distinction lies in the ability of CD8⁺ T cells to be engaged by pro-inflammatory LAMP⁺ DCs, which are localized to TLS in NSCLC, but not ccRCC. Together, these findings indicate that extrinsic factors significantly impact T cell function and that targeting mechanisms to support the ongoing function and appropriate trafficking may help to control these apparently T cell-resistant tumor types.

Beyond the composition of the individual tumor, the site of tumor growth and metastasis can contribute to immune privilege or tumor control. Comparing tumors at secondary sites, Paul Tumeh of the UCLA Jonsson Comprehensive Cancer Center (Los Angeles, USA) demonstrates that metastatic melanoma in the liver, but not lung, is associated with poor prognosis and responses to anti-PD-1 therapy, and suggests that metastatic tumors may be co-opting the liver as a site of tolerogenesis and immune privilege. Liver metastatic nodules are TIL-poor, and infiltrating T cells express both CTLA-4 and PD-1. Extending from these findings, the site of metastases may provide clues for precision medicine and prognosis.

Clearly, there is an urgent need to relieve the immunosuppression in the tumor microenvironment to foster successful immunotherapy. Keynote speaker Ronald Levy from Stanford University (Stanford, USA) demonstrated that this could be accomplished by injecting inflammatory agents, such as CpG, at the tumor site in combination with chemo- or radiation therapy. This approach toggles the microenvironment from immunosuppressive to pro-inflammatory. Further, it prompts epitope spreading, where the antigens from lysed tumor cells become targets for a broadening T cell-mediated anti-cancer response. This approach—to “inject locally, treat globally”—generates nascent effector T cells that are not restricted to the primary tumor site. In the first clinical trials, co-injection of CpG with chemotherapy was beneficial to eliminate distal metastases in 25 % of patients. Though promising, this outcome implies that additional, complementary interventions to control suppressive populations may be necessary. This could be achieved by the use of the combination of anti-CTLA-4 and anti-OX40 antibodies to control Treg and follicular dendritic cell-mediated immunosuppression. Current clinical trials for B cell lymphoma combine intratumoral anti-CTLA-4 with CpG and local low-dose irradiation.

Redirecting immunosuppression to evoke inflammation could further enhance anti-tumor efficacy. Levy is additionally trialing ibrutinib, a small molecule that binds to the lymphocyte tyrosine kinase, BTK, as well as JAK3, CSK, YES, LCK and other tyrosine kinases. By interfering with signal transduction in lymphocyte populations, it is possible to shift from a Th2 to a Th1 environment and support cytotoxic T cell activity. Combinations of in situ vaccination with systemic strategies to facilitate enhancement of ADCC were also mentioned by Greenberg. In ongoing clinical trials, combinations of tyrosine kinase inhibitors (ibrutinib), intratumoral CpG administration, PD-L1 blockade and/or 4-1BB agonists are being considered to facilitate maximal anti-tumor immunity. A different approach is to co-opt the inhibitory signaling pathways by engineering inhibitory receptors to express the intracellular activating domains of co-stimulatory molecules. In this clever approach, when an engineered T cell encounters an inhibitory ligand from the microenvironment (PD-L1 for example), receptor engagement is co-opted to stimulate T cell effector function.

Agonistic antibody-based treatment strategies

The lack of co-stimulation and the active repression through inhibitory receptors found within the tumor microenvironment or associated lymphoid tissue presents a significant barrier to the success of cancer immunotherapy. Strategies to block checkpoint inhibition (e.g., anti-PD-1 or anti-CTLA-4) or agonize co-stimulatory molecules (e.g., OX40) are important immunotherapeutic strategies that can increase the efficacy of anti-cancer immunity. Skewing the balance of signals toward activation, rather than inhibition, is improving prognosis in patients with several types of cancer. Further, predicting the outcome of antibody-based immune therapies will assist in precision medicine to appropriately guide the anticancer immune response.

Work from Andrew Weinberg’s laboratory at The Providence Cancer Center, Portland, USA, suggests that combining therapies that interrupt inhibition with those that stimulate T cell function will be most effective. In murine models, agonizing TIL with OX40 agonists promotes the formation of memory T cell subsets that are capable of tumor control upon rechallenge. Anti-OX40 treatment induced increased CD4⁺ and CD8⁺ T cell proliferation, durable 28 days after antibody administration was stopped, as well as recruitment of T cells to gliomas, colorectal cancer and sarcomas in murine models. Furthermore, they demonstrated a synergistic effect of dual therapy using anti-OX40 in combination with SM16 (a TGF-β receptor inhibitor) when an anti-tumor immune response is present but suppressed. The combination strategy led to an increase in IFN-γ-producing T cells and proliferating (Ki67⁺) CD8⁺ TIL associated with full regression of established tumors in murine models. Weinberg further demonstrated that the combination of co-stimulatory agonism (OX40) and interruption of inhibition (anti-PDL-1) enabled more receptor cross-linking and stronger T cell activation. Whether this combined approach will have the same impact in patients with cancer remains to be determined in future clinical trials.

In addition to supporting T cell-mediated tumor cytotoxicity, recruitment of NK cells will foster enhanced local tumoricidal activity and provide complementary surveillance against tumor cells expressing diminished levels of MHC. Anti-4-1BB antibody has well-known co-stimulatory activity on T cells, but can also be used to stimulate cytotoxic activity of NK cells. For this purpose, Levy is now coupling agonistic anti-4-1BB with existing cancer therapies for lymphoma, breast and colon cancer with promising early results. Ongoing trials have achieved partial and complete responses, supporting anti-4-1BB antibody as a complementary approach to other monoclonal therapies.

A high density of CD8⁺ T cells is associated with good outcomes in most cancers and supports therapy using checkpoint inhibitors or agonistic antibodies to stimulate immune function. However, as described by Radvanyi, even though checkpoint inhibition therapy has proven to be very successful, still about forty percent of melanoma patients progress after therapy, suggesting that escape mechanisms from this regimen exist. Therefore, identification of novel therapeutics and establishment of combinatorial strategies using antibody-based therapeutics, adoptive cell therapies and chemotherapeutics may be required to improve overall outcomes.

Bioinformatics and precision medicine

Tumors, even those of the same origin, differ in their ontology and consequently, susceptibility to various therapeutic interventions. An important goal in precision and personalized medicine is to identify tumor-specific weaknesses that can be exploited for effective therapy. Increasingly, high-throughput sequencing technologies and bioinformatics are critical tools to assess tumor genetics and transcriptomes to a resolution sufficient to inform therapeutic decisions. Understanding cancer at this level is increasing the precision of therapy and identifying future therapeutic targets.

Predicting outcomes to checkpoint blockade therapy

With increasing availability of monoclonal antibodies, ease of use and development, it is becoming possible to tailor the tumor microenvironment with off-the-shelf tools. Understanding how to predict the outcomes of checkpoint blockade therapy will inform treatment strategies targeted to the mutations and suppression present in individual tumors.

Tumeh demonstrated that the success of anti-PD-1 therapy for melanoma can be predicted using an algorithm created by performing multiple linear regressions analysis based on immune and disease parameters. Specifically, a high density of CD8⁺ T cells at the tumor invasive margin and the absence of liver metastases are associated with the best prognosis and response to therapy. To a less significant extent, clonal populations and Ki67⁺ CD8⁺ T cells predicted for improved outcomes. Surprisingly, however, neither CD4⁺ T cell density nor PD-L1 expression could predict anti-tumor efficacy.

Harlan Robins from the Fred Hutchinson Cancer Research Center (Seattle, USA) described another method to predict the response of anti-PD-1 therapy using high-throughput analysis to determine the clonality of TIL by sequencing BCRs and TCRs. They found that clonal expansion following anti-PD-1 therapy in patients with melanoma is associated with improved therapeutic response and better prognosis. When genomics approaches reveal poor expansion of TIL after anti-PD-1 therapy, further interventions would be indicated to boost lymphocyte proliferation and function. Combination strategies that can be of use in this regard include vaccines, BRAF inhibitors, anti-CTLA-4 or radiation.

Despite consistency among the antigens of a given tumor type, the ideal targets for immunotherapy have not been fully elucidated. Increasingly apparent is a need to cater personalized therapies against the antigens available on a given tumor, with an emphasis toward targeting antigens that represent cancer stem cells or driver mutations. The majority of traditional cancer characterizations are based on phenotype and histology, rather than the functional and genomic mutations underlying each cancer, which may better inform precision and personalized approaches to cancer therapy. At the BC Cancer Agency (Vancouver, Canada), Christian Steidl is characterizing the genetic features leading to lymphoma to determine how best to treat patients. For instance, he has demonstrated that the identification of common driver translocations involving CIITA and structural alterations of the PD-L1 or PD-L2 locus lead to downregulation of MHC class II molecules and increased expression of PD-L1 and PD-L2, respectively, generating somatically acquired immune privilege. Patients whose tumors harbor these and other genomic alterations (i.e., in B2M, CD58, TNFRSF14, CIITA, PD-L1 and PD-L2) affecting tumor microenvironment interactions may be ideal candidates for PD-1 inhibition or other therapies with drug targets expressed on non-malignant host cells. With the goal of developing companion diagnostic approaches, Steidl advocates that mutational or related phenotypic testing be included in future clinical trial designs.

Sequencing and genomics to personalize therapy

With the increasing availability of whole- and tumor-genome sequencing, high-throughput assessment and computational analysis, bioinformatic approaches to cancer immunotherapy are feasible. Sohrab Shah and Marco Marra of the BC Cancer Agency in Vancouver, Canada, are using sequence-based approaches to understand the evolution of a tumor using genomics approaches, identify driver mutations and direct immunotherapy. Shah described the “clonal evolution theory” which identifies mutations that have facilitated the clonal expansion of tumor cells. Integrating high-throughput next-generation sequencing (NGS), digital PCR (dPCR) and a murine model of breast cancer for validation, his group has demonstrated that it is possible to identify driver mutations on an individual cell basis. With a similar goal, Marra is using whole-genome and whole-tumor sequencing, together with bioinformatics, to identify the earliest driver mutations common among the outgrowing tumor populations.

Marra discussed the challenge of using large data sets of gene expression profiles, single mutations or groups of related mutations to identify “actionable” targets for personalized therapy. Using panels of key cancer genes to identify genomic changes has been successful (e.g. Memorial Sloan Kettering’s Integrated Mutation Profiling of Actionable Cancer Targets, MSK-IMPACT), but this approach is biased and may fail to capture the heterogeneity of tumors and/or rare mutations. Marra described a pilot project—personalized oncogenomics (POG)—to develop a pipeline to utilize genomic data to direct the treatment course. The process involves generating a disease–gene–drug interaction knowledgebase populated by genomic and transcriptome data from patients. The mutations in patient tumors, identified through whole-genome or whole-tumor sequencing, are screened through this database and discussed by a panel of physicians and scientists to direct the therapeutic path. This process has identified actionable mutations in 55/100 patients tested so far, with 14 of the 34 patients given POG-informed therapies demonstrating clinical or radiographic improvement following treatment. POG-informed therapy is in its infancy, but with an increasing cohort size, the database against which tumor genomes are queried is improved, and the time to treatment shortened. Thus, this approach is a highly feasible future direction in personalized cancer immunotherapy.

The next phase in immunotherapy will depend on determining mutational load and a matching immune signature in each patient in order to direct the course of therapy. Julie Nielsen, speed poster presenter and second place poster winner, from Brad Nelson’s laboratory at the BC Cancer Agency’s Deeley Research Centre, in Victoria, Canada, showed that NGS for common driver mutations in follicular lymphoma could identify those relevant to individual patients. Extending from these findings, T cells could be assessed for their reactive potential, allowing Nielsen and Nelson to predict the likelihood of T cell-mediated control and endorse further ex vivo expansion to support T cell-based immunotherapy targeting mutations.

An exciting application of high-resolution sequencing technology, described by Kai Wucherpfennig of the Dana Farber Cancer Institute (Boston, USA), involves its use to identify pathways relevant to the function of cytotoxic T cells. Using bar-coded and Thy1.1-labeled lentiviral constructs encoding shRNAs and comparing transduced T cells from tumors and spleens of mice, he identified novel pathways inhibiting T cell function in the tumor microenvironment. Using this technology, he has identified Ppp2r2d, a regulatory subunit of the PP2A family of phosphatases, as a mechanism for inhibiting T cell expansion and survival in tumors. Silencing of this gene enhances cytokine production in T cells and enhanced anti-tumor efficacy. This gene may represent a novel target for enhancing the efficacy of adoptive T cell therapies. Moreover, this study highlights the potential of systematic in vivo approaches for discovery of the next generation of targets for immunotherapy.

Conclusion

Although the potential of the immune system to detect and eliminate tumor cells has long been recognized, the technologies, expertise and approaches required to direct anti-cancer immunity are only now becoming accessible. Immunotherapy has shown major successes in recent years, and the future looks promising. New approaches for in-depth analysis of molecular mechanisms of tumorigenesis, combined with gene signatures of the tumor, tumor microenvironment and immune components will provide rationale for new and combination therapies ultimately with the single goal of improving patient outcome. Increasingly, the potentials and limitations of each approach are being understood and are informing intelligent approaches to personalized medicine.

The CCIC is a relatively young association (founded in 2008), dedicated to the scientific advancement of immunotherapy of cancer. This 8th meeting was the largest to date, reflecting an increasing interest in and promise of immune-based cancer therapeutics. The many successes reported by world-class investigators inspire optimism and collaboration for members of the CCIC and beyond. The poster and speed poster presentations, outstanding invited speakers and highly social atmosphere collectively make this Canadian-led consortium an important networking and training environment necessary to advance the research and development of immunotherapies for cancer. The next meeting will be held June 26–29, 2016 in Halifax, Nova Scotia.

Abbreviations

AdV

Adenovirus

BTK

Bruton’s tyrosine kinase

CAR-T

Chimeric antigen receptor T cell

CCIC

Canadian Cancer Immunotherapy Consortium

ccRCC

Clear cell renal cell carcinoma

CMV

Cytomegalovirus

CSK

c-Src kinase

DC

Dendritic cell

dPCR

Digital polymerase chain reaction

EBV

Epstein–Barr virus

INSERM

Institut National de la Santé et de la Recherche Médicale

JAK3

Janus kinase 3

JC

John Cunningham virus

LAMP

Lysosomal-associated membrane protein

LCK

Lymphocyte-specific protein tyrosine kinase

MDSC

Myeloid-derived suppressor cells

NGS

Next-generation sequencing

NK

Natural killer

NSCLC

Non-small cell lung carcinoma

POG

Personalized oncogenomics

TAM

Tumor-associated macrophages

TCR

T cell receptor

TIL

Tumor-infiltrating lymphocytes

TLS

Tertiary lymphoid structures

Treg

Regulatory T cell

VST

Virus-specific T cell

VZV

Varicella zoster virus

YES

Cellular homolog of the Yamaguchi sarcoma virus oncogene

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest. Connie Krawczyk participated in the organization of this CCIC meeting as coordinator of knowledge dissemination and outreach.