The development of effective and free of side effects immunization against cancer is a puzzling and open issue in research. One of the major problems is the weakness of immune responses against tumor-associated antigens (TAAs) which are usually recognized by the immune system as self-antigens. However, tumor cells express multiple neoantigens, which are specific for each tumor and most of the times specific for each individual. Neoepitopes develop in cancer cells through point mutations, insertions/deletions, amplifications/deletions, translocations, inversions etc [1]. Since neoepitopes are exempted from central tolerance, the development of specific high-affinity T cells could be achieved. Once a neoepitope is selected, the patient’s individual vaccine could be manufactured. Indeed, mutation-based vaccination could indentify multiple shared neoantigens, including mutRas, mutP53, mutVHL, mutEGFR, or mutIDH1 [1], which could be used for diagnosis and amendment of therapeutic vaccination protocols. Yet, the introduction of next generation sequencing technologies (NGS) revealed that human cancers were much more complicated, carrying thousands of mutations which could provide potential MHC class I neo-epitopes [2,3]. Mapping the entire somatic mutations of an individual tumor, referred as “mutanome”, could allow the selection of neoepitopes. However, population common neoantigens have been unsuccessfully used in vaccine technologies. In such case, vaccine failure lies on the neoepitope, carrier and adjuvant or cross-linking to biodegradable materials, theoretically designed to target the tumor, selection.

The following efforts to fight intrinsically malignant cells focused on the isolation or engineering of tumor antigen-specific autologous T cells. Such adaptive cell transfer (ACT) therapies include the use of tumor infiltrating lymphocytes (TILs), the engineering of patients T cells to express specific T cell receptors (TCRs) or fragments of synthetic antibodies that recognize tumor epitopes linked to various co-stimulators on the cell surface, known as chimeric antibody receptors (CARs) [4]. Although promising, the high cost, the long waiting time and the questionable effectiveness make these technologies inaccessible to a high percentage of patients.

As a step beyond these laborious, but expensive, time-consuming, and of limiting effectiveness strategies, ImmunoRec concentrates on the application of the personalized implantable vaccine technology [5]. According to this strategy, a biomimetic platform is used to attach autologous macrophages, which upon stimulation with the appropriate dose of the patient’s “mutatome” in vitro and hypodermal implantation leads to the production of tumor-specific T and B cells attacking the tumor.

The application of the Personalized Implantable Vaccine technology in cancer immunotherapy stimulates humoral as well as cellular immune response against the specific tumor of each individual.

The use of non-biodegradable implants avoids the adjuvant-dependent side-effects, while providing the necessary immune stimulation to the patient [6]. The technology applied by ImmunoRec allows recipient APCs to present tumor’s “mutanome”, ensuring thus best neoantigen presentation for each individual. Laboratory screenings prior to implant construction determine the best conditions for the responsiveness of each patient, avoiding tolerance, overcoming suppression and ensuring conditions of specific immune stimulation.

In cancer immunotherapy, the application of the implantable vaccine technology includes 5 stages:

  • Patient’s biopsy: No special intervention is needed, because all patients at some stage of the disease have been submitted to solid tumor sampling. No fresh biopsy is needed. Cell extracts are obtained without the use of chemicals or enzymes.
  • Determining patient’s antigenicity to tumor extract: Blood collection from the patient for white cell isolation and testing. This step will determine the most effective dose of the tumor extract to be used for the patient. The tumor cell extract contains all neoantigens of the specific tumor, against which the immune system will be able to mount a cellular and humoral immune reaction. Finding the right immunogenic dose of the extract is essential, because it should also outweigh the possible suppression that the patient may have developed against these neoantigens.
  • Cell loading to the microstructured silicon scaffolds: Blood collection for isolation and culture of white blood cells on top of microstructured silicon scaffolds.
  • Activation of the adherent cells: The immunogenic dose of tumor extract determined from step 2 is provided to the adherent cells of step 3. After the 24-hour incubation, the non-adherent cells are removed and the culture medium is replaced by fresh medium containing the appropriate dose of tumor cell extract, as defined in step 2.
  • Subcutaneous implantation of the activated silicon scaffold to the patient and monitoring of efficacy. The effectiveness of the procedure is apparent one week after implantation.

The design of the personalized implantable vaccines has been carried out within the context of maximal safety for the patient, absence of side effects and minimal burden for the body.

  • The use of autologous peripheral blood cells ensures the absence of any graft rejection reactions.
  • The use of the patient’s own biopsy ensures the specificity of the reaction against the specific tumor, while at the same time avoiding any allogeneic reactivity.
  • The ex-vivo activation of the autologous cells with the tumor cell extracts allows determination of the optimal conditions for the desired response.
  • The choice of a non-biodegradable material as a platform for creating a system resembling a secondary lymphatic organ on-chip, ensures the absence of by-products with unknown side effects.

[1] Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, Sahin U. Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines. Clin Cancer Res. 2016; 22(8):1885-96.

[2] Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope landscape in breast and colorectal cancer. Cancer Res 2008; 68:889–92.

[3] Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 2015;520:692-6.

[4]  Sukari A, Abdallah N, Nagasaka M. Unleash the power of the mighty T cells-basis of adoptive cellular therapy. Crit Rev Oncol Hematol. 2019; 136:1-12. doi: 10.1016/j.critrevonc.2019.01.015.

[5] Zerva Ι, Simitzi C, Stratakis E, Athanasakis I. Personalized Implantable Vaccines with Antigen PreActivated Macrophages. Austin J Clin Immunol. 2019; 6(1):1038

[6] Zerva I, Simitzi C, Siakouli-Galanopoulou A, Ranella A, Stratakis E, Fotakis C, Athanassakis I. Implantable vaccines: In vitro antigen presentation enables in vivo immune response. Vaccine, 2015; 33: 3142–3149.