Title: Breakthrough in Cancer Immunotherapy: Overcoming Barriers to Treat Solid Tumors
Introduction:
Cancer immunotherapy has revolutionized cancer treatment, significantly improving patient survival and quality of life. The success of adoptive T cell and immune checkpoint inhibitor therapies has been remarkable. However, the efficacy of adoptive T cell therapies in treating solid tumors, which constitute approximately 90% of all tumors, has been limited due to various challenges. Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a novel immunotherapy approach called SIVET (synergistic in the place enhanced T-cell vaccination), which has the potential to overcome these barriers and provide effective treatment for solid tumors. This article explores the development of SIVET and its promising results in preclinical studies.
Understanding the Challenges in Treating Solid Tumors:
Adoptive T cell therapies involve modifying a patient’s T cells outside the body so that they can target specific antigens on tumor cells. However, when these modified T cells are reintroduced into the patient’s bloodstream, they face several obstacles in reaching and effectively attacking solid tumors. These challenges include long distances to travel, difficulty in infiltrating the tumor mass, suppression of cytotoxic activity by tumor cells and the surrounding microenvironment, and increasing heterogeneity of tumor cell surface antigens.
Introducing SIVET: A Biomaterials-Based Immunotherapy Approach:
The team of immunoengineers at Harvard University has developed a groundbreaking approach called SIVET. It combines the benefits of adoptive T cell therapy and cancer vaccine technology in a locally delivered biomaterial. SIVET allows for the local delivery of antigen-specific T cells to tumor sites, their prolonged activation, and engagement of the host’s immune system to provide longer-lasting antitumor effects against new antigens carrying tumor cells. The biomaterial used in SIVET is an injectable cryogel containing collagen and alginate polymers crosslinked on a porous scaffold.
How SIVET Works:
Once the engineered T-cell reservoir is injected near the tumor site, the compressed biomaterial returns to its original shape and starts releasing cytokines that facilitate the expansion of administered T cells. These T cells move out of the biomaterial and attack the tumor cells. Additionally, the biomaterial releases another cytokine that attracts host antigen-presenting cells (APCs) to the scaffold. The APCs are concentrated and activated with the help of a helper molecule near the tumor, leading to a more extensive immune response against the tumor.
Promising Results in Preclinical Studies:
In preclinical studies using a mouse model of melanoma tumors, SIVET demonstrated superior control over tumors compared to direct injection of T cells or infusion into the bloodstream. The biomaterial allowed administered T cells to remain active longer and prevented depletion of all T cells in the tumor microenvironment. SIVETs trained the immune system to reject melanoma tumors for prolonged periods, resulting in significantly improved survival compared to control treatments.
Implications and Future Directions:
The SIVET approach holds immense promise in addressing the limitations of current immunotherapies and advancing the treatment of solid tumors. The synergistic combination of adoptive T cell therapy and cancer vaccine technology, facilitated by the biomaterial, enables rapid reduction of tumor masses and deeper engagement of the immune system. Further research is required to validate SIVET in clinical trials and explore its potential for treating other types of solid tumors.
Conclusion:
The breakthrough development of SIVET offers new hope in the field of cancer immunotherapy, particularly for the treatment of solid tumors. This innovative biomaterial-based approach has the potential to overcome the barriers that limit the efficacy of adoptive T cell therapies. By combining two powerful immunotherapy approaches, SIVET provides rapid tumor reduction while engaging the immune system at a deeper level. Further advancements in this field could pave the way for more effective and personalized treatments for cancer patients.
Summary:
Breakthrough research from Harvard University’s Wyss Institute and SEAS has led to the development of SIVET, a novel immunotherapy approach for solid tumors. SIVET combines adoptive T cell therapy with cancer vaccine technology in an injectable biomaterial. This biomaterial allows for the localized delivery of T cells to tumor sites and their prolonged activation. It also promotes a broader immune response against new antigens on tumor cells. Preclinical studies using a mouse model of melanoma tumors have shown promising results, with SIVET demonstrating improved tumor control and prolonged survival compared to existing treatments. Future research aims to validate SIVET in clinical trials and explore its potential for treating other solid tumors. This breakthrough offers new hope for cancer patients and could revolutionize cancer immunotherapy.
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Cancer immunotherapy has brought significant improvement in patient survival and quality of life, especially with the success of adoptive T cell and immune checkpoint inhibitor therapies. Unfortunately, in contrast to different types of blood cancers, the efficacy of adoptive T-cell therapies in the treatment of solid tumors, which comprise approximately 90% of all tumors, has been very limited due to several formidable barriers.
In adoptive T-cell therapies, a patient’s T cells with cytotoxic potential are modified outside the body so that they can bind to specific features (antigens) on the surface of tumor cells, turning them into tumor-killing cells. However, after being reinfused into the donor patient’s bloodstream, they have to travel long distances to reach a solid tumor, and only a fraction of them ever get there. At the site, they need to infiltrate the often difficult-to-penetrate tumor mass while their cytotoxic activity is suppressed by tumor cells and the surrounding tissue microenvironment. In addition, the larger solid tumors grow, the more heterogeneous their cellular composition becomes, which also includes the repertoire of tumor cell surface antigens and thus allows them to “escape” attack by adoptively transferred T cells.
Now, a team of immunoengineers from Harvard University’s Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new biomaterials-based immunotherapy approach called SIVET (short for “synergistic in the place enhanced T-cell vaccination”) that has the potential to break down these barriers. The injectable biomaterial allows both: local delivery of antigen-specific adoptively transferred T cells directly to tumor sites and their prolonged activation, as well as broader engagement of the host’s immune system to provide much longer-lasting antitumor effects against tumor cells carrying new antigens. Validated in mice carrying melanomas, a particularly aggressive type of solid tumor, SIVET enabled rapid shrinkage of tumors and long-term protection. term against them. The findings are published in nature communications.
“In the SIVET approach, we essentially combine fast-acting adoptive T cell therapy with long-term protective cancer vaccine technology in a locally delivered integrated biomaterial. Advancing this approach towards patient environments could help to addresses several limitations of current immunotherapies and offers new advances in the treatment of solid tumors,” said lead author David Mooney, Ph.D., a founding faculty member of the Wyss Institute and the Robert P. Pinkas Family Professor of Bioengineering in MARES. Mooney directs the Wyss Institute Immunomaterials Platform and co-directs the NIH-funded Immuno-Engineering to Improve Immunotherapy (i3) Center coordinated at the Wyss Institute and focused on creating biomaterials-based approaches to enable cancer immunotherapy in solid tumor settings.
Biomaterials convergences
In previous extensive work, Mooney’s team had pioneered biomaterial-based cancer vaccines that can program key immune-orchestrating dendritic cells, known as antigen-presenting cells (APCs), into tumor-fighting cells. live. Although cancer vaccines can provide broad therapeutic and prophylactic benefits, their tumor-directed effects take time to manifest in the body. On the other hand, patient-specific adoptively transferred T cells are primed to attack tumor cells on first contact, but produce short-lived responses.
“Our new platform takes full advantage of our experience with cancer vaccine and adoptive T cell technologies. Combining the best of these two worlds in a multi-pronged biomaterials-based approach enables rapid reduction of existing tumor masses.” while engaging the immune system at a much deeper level through localized delivery, concentration and activation of various tumor-fighting immune cells,” said co-author Kwasi Adu-Berchie, Ph.D., who completed his Ph.D. in Mooney’s lab and is currently a translational immunotherapy scientist at the Wyss Institute.
Adu-Berchie, Mooney, and team developed a cryogel biomaterial containing collagen and alginate polymers crosslinked on a three-dimensional porous scaffold. While the alginate provides structural support to the biomaterial, the collagen serves to provide the ligands necessary for T-cell trafficking. Following injection of the engineered T-cell reservoir near the tumor site, the compressed biomaterial returns to its original shape and begins to release the cytokine interleukin 2 (IL2) to facilitate the expansion of the administered T cells, which move out of the biomaterial and into the tumor to carry out an attack.
Furthermore, the biomaterial releases a second cytokine, abbreviated as GMCSF, which attracts host APCs to the porous scaffold which are then also concentrated and activated with the help of a helper molecule known as CpG near the tumor. Activated APCs also infiltrate the tumor mass where they take up new antigens created by dying tumor cells that disintegrate as a result of T cell attack. APCs then migrate to nearby lymph nodes where they orchestrate a more extensive response to the tumor. vaccine by presenting processed antigens to other types of immune cells, including other cytotoxic T cells that attack the tumor in consecutive waves, as well as memory T cells that wait in the future. recurrences
The researchers investigated SIVET in a mouse model of melanoma tumors and found that the multifunctional biomaterial allowed better control over tumors than the same adoptively transferred T cells injected directly into the tumor site or infused into the animals’ bloodstreams. SIVETs allowed administered T cells to remain active longer and minimized depletion of all T cells in the tumor microenvironment compared to control conditions.
“Through their vaccine component, SIVETs trained the immune system to reject melanoma tumors for significantly prolonged periods of time, and therefore allowed animals to survive much longer than animals given any of our vaccines.” control treatments. This was likely facilitated by the biomaterial’s ability to prevent the growth of tumor cells that escape attack by adoptively transferred T cells due to their loss of target antigen initially,” Adu-Berchie said. “Identifying a tumor-specific antigen against which potent donor-specific T cells can be generated for adoptive transfer could provide SIVETs with enough to initiate a tumor attack on a much broader front and scale.
“This study is a beautiful convergence of two powerful immunotherapy approaches that are programmed in the body to synergize with each other. This work once again demonstrates the power of taking an unconventional transdisciplinary approach, in this case combining strategies from scientific of materials. and tissue engineering with immunology, to create novel and more powerful therapies for the eradication of solid cancers,” said Wyss Founding Director Donald Ingber, MD, Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Children’s Hospital Boston, and the Hansjörg Wyss Professor of Bioinspired Engineering in MARES.
The study is also written by other past and present members of Mooney’s group, including Joshua Brockman, Yutong Liu, Tania To, David Zhang, Alexander Najibi, Yoav Binenbaum, Alexander Stafford, Nikolaus Dimitrakakis, Miguel Sobral, and Maxence Dellacherie. It was supported by grants from the National Institutes of Health (award #U54 CA244726 and #U01 CA214369), the National Science Foundation (award #MRSEC DMR-1420570), and the Food and Drug Administration (award #R01 FD006589), as well as the National Cancer Institute (award #5K00CA234959).
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