Adoptive cell transfer Melero et al. In the first case, lymphocytes derived from the resected tumors tumor infiltrating lymphocytes, TILs are infused unmodified back into patients after in vitro expansion; in the second case, autologous peripheral blood lymphocytes are genetically engineered to recognize specific tumor antigens [T-cell receptors TCR or chimeric antigen receptor CAR ].
These T cells can mediate tumor destruction once expanded and reinfused into the patients. Using this approach a long lasting response with complete tumor regression has been observed in metastatic melanoma patients Rosenberg et al. However, over the years this approach has shown its limitations because it seems to be primarily restricted to melanoma patients and few other tumors characterized by strong immunogenicity due to high frequency of mutational events Lawrence et al.
Unfortunately, to obtain tumor eradication this approach needs often to be associated with preparative lymphodepletion by chemotherapy alone or in combination with total body irradiation and IL-2 administration, two treatment regimens that are not always suitable for all patients Dudley et al. In contrast, engineered T cell therapy is experiencing promising developments in light of spectacular results seen in patients with B cell malignancies Amrolia and Pule, ; Kochenderfer et al.
Genetically modified T cells TCRs and CARs have been developed to overcome the consequences of immune tolerance or immune suppression generated on tumor-specific T cell repertoire. Although promising results have been obtained in metastatic melanoma patients using TCRs with specificity for MART1 or other melanoma antigens Johnson et al.
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On the contrary, CAR T cells have antibody-like specificities and can recognize MHC-non-restricted structures on the surfaces of target cells. CAR T cells are constructed by fusing an antibody against a tumor surface antigen to the TCR intracellular domains capable of activating T cells June et al. Once modified, CAR T cells are expanded and infused back to lymphodepleted patients where they can eradicate the tumor. New generation CARs have been developed in order to include the intracellular domains of one or more co-stimulatory molecules, such as CD28 or OX40 June et al.
This approach has demonstrated remarkable efficacy in hematological tumors, in particular B-cell malignancies treated with CAR T cells with specificity for CD19 Kochenderfer and Rosenberg, In contrast, its effectiveness and safety in solid tumors still need to be proven in part due to the difficulties to find target antigens with limited or no expression in normal tissues and in part for the tumor immunosuppressive microenvironment TME.
However, encouraging results have been reported in neuroblastoma Louis et al. Thus, adoptive T cell transfer is a highly promising immunotherapy that needs to be optimized to reduce toxicity and to enhance anti-tumor efficacy. Combination with immune checkpoint blockade to remove T cell inhibitory stimuli could further potentiate the activity of CAR T cells Batlevi et al. The idea to stimulate the immune system to treat cancer dates back to 19th century.
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Although promising results obtained in preclinical models over the years, the field of therapeutic cancer vaccination in humans has shown modest success so far Melero et al. To date, only a single cancer vaccine was FDA-approved Kantoff et al. Although many issues in therapeutic cancer vaccination are still an open debate, such as the identification of right tumor antigens or right adjuvants and delivery vehicles or the immune suppressive microenvironment that dampens an anti-tumor response, recent developments in cancer immunology and therapy have revitalized the field.
Also targeted therapy can act synergistically with cancer vaccination as some of these drugs have shown immunomodulatory activities Balachandran et al. In addition, targeted therapy can reduce tumor burden without adversely affecting the immune system and provide the optimal setting of minimal disease for cancer vaccination. Several studies on mouse models and a phase I clinical trial provided a strong rationale for the development of neoantigens as a therapeutic approach in human cancer Carreno et al.
However, the use of neoantigens in humans is still challenging for several reasons; first, the identification and selection of immunogenic neoantigens need high technology laboratories; second, neoantigens correlate with tumor mutational load and thus are mostly restricted to highly mutated tumors; third neoantigens are patient-specific and thus require the development of a patient-specific vaccine that can be time-consuming and expensive; fourth, the correct vaccine strategy to elicit maximal immunity needs to be tested, such as cell-based vaccines using dendritic cells or peptide-based vaccines.
In contrast to targeting neoantigens, cancer vaccines can also be directed against antigens that are shared by a large number of cancers shared antigens. A long series of shared antigens have been proposed for cancer therapy Cheever et al. Some of these antigens have been evaluated in therapeutic vaccination in different tumors and in some cases survival advantages have been reported Melero et al.
Among these, the Wilms tumor -1 WT-1 , a transcription factor involved in cell proliferation, differentiation, and apoptosis , has been tested as cancer antigen in acute myelogenous leukemia AML and breast cancer patients. In both cases vaccination with WT-1 led to tumor partial regression Melero et al.
In these tumors, ALK is specifically expressed by tumor cells with very low and limited expression in normal tissues, and it is required for tumor survival and growth, which greatly decreases the chances of ALK negative clones to escape the immune system Hallberg and Palmer, ; Mastini et al.
Interestingly, the presence of a specific immune response to ALK is associated with a decreased risk of relapse in lymphoma patients Ait-Tahar et al. Immunotherapy aimed at inducing an anti-tumor immune response has now potently entered in the armamentarium to treat cancers. To rationally develop new therapeutic strategies that would maximize the efficacy of immunotherapy alone or in combination with other current cancer treatments, it is important to better understand different aspects of tumor biology , such as the dynamic nature of the interaction between the immune system and the tumor, the constant evolution of the anti-tumoral immune response, and the evolving genetic landscape of tumors.
This work was supported by the following grants to R. Cancer Res 67 5: Int J Cancer 3: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Amrolia PJ, Pule M.
Chimeric antigen receptor T cells for ALL. The three main stumbling blocks for anticancer T cells. Trends Immunol 33 7: Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
Nat Med 17 9: Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 13 1: Tumor antigens recognized by T lymphocytes. Annu Rev Immunol Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med Combinations in the Clinic.
A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Exploiting the mutanome for tumor vaccination. Cancer Res 72 5: The receptors CD96 and CD oppose each other in the regulation of natural killer cell functions. Nat Immunol 15 5: The prioritization of cancer antigens: Clin Cancer Res 15 Chen DS, Mellman I. The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.
Nat Med 14 6: Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity.
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