Employing Advanced Therapy Medicinal Products in Oncology
Daniel Kavanagh, PhD, RAC, Senior Scientific Advisor, Gene Therapy, Vaccines, and Biologics, WCG
Personalized medicine uses specific information about an individual's biology to design treatments specifically tailored for them. In oncology, cell and gene therapy (CGT) encompasses an array of clinical approaches harnessing molecular medicine, synthetic biology and/or living human cells. Clinical trials combining these approaches for the treatment of cancer are advancing rapidly.
Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues, or cells. This category is largely overlapping with that of cell and gene therapy (CGT) products, which is the terminology usually used in the U.S. and by the U.S. Food and Drug Administration (FDA). Many ongoing clinical trials are testing ATMPs in a broad range of therapeutic areas, including oncology, ophthalmology, cardiology, rheumatology, and many rare and ultra-rare diseases. In oncology, the most prominent CGT modalities under development include genetically modified immune effector cells, oncolytic viruses, viral vector vaccines, and nucleic acid vaccines.
Immune Effector Cells (IECs)
IECs are white blood cells capable of effecting antitumor responses and killing cancer cells. The best-known IEC products in oncology are Chimeric Antigen Receptor T (CAR-T) cells. Multiple CAR-T cell products have marketing approval for clinical use in the EU and in the U.S. All the first-generation CAR-T products are autologous cellular products, manufactured for each patient using precursor T cells derived from that person’s own blood.
Aside from T cells, other types of white blood cells are also being tested as IECs. These include natural killer (NK) cells modified with chimeric antigen receptors similar to those used for CAR-T. Like T cells, NK cells are a class of lymphocytes that specialize in killing tumors and virus-infected cells. However, in many cases the CAR-NK cell products in development are not autologous; instead, they are allogeneic (“allo”) cell products derived from a healthy blood donor. Another type of white blood cell being tested as a potential allogeneic IEC is macrophage leukocytes—these cell products are referred to as CAR-M cells. Historically, genetic modification of IECs has been accomplished with older gene transfer technologies, such as viral vectors. Many new clinical trials include IECs genetically modified with cutting-edge gene editing technology, notably using CRISPR-based approaches.
Oncolytic Viruses
In addition to these cellular therapies, many CGT products under development are based on genetically modified viruses. In many cases the virus is engineered to preferentially reproduce in cancer cells rather than in healthy tissue—resulting in an oncolytic virus capable of destroying tumor cells. The most effective oncolytic viruses exert a multipronged antitumor effect not only by killing cancer cells directly, but also by disrupting the tumor microenvironment (which may be immunosuppressive), by activating nearby immune cells, and by priming immune response to proteins found in cancer cells (tumor antigens).
Cancer Vaccines
Cancer vaccines do not rely on the direct killing of a tumor but rather focus on priming immune responses against tumor antigens. Some cancer vaccines under development are based on mRNA, very similar to the mRNA vaccines approved for prevention of COVID-19, or on DNA. DNA and RNA based vaccines are nucleic acid vaccines.
Many cancer vaccines under development are based on genetically modified viral vectors that express a tumor antigen. Sometimes the viral vector vaccine is intended to infect cells away from the tumor site in order to prime a systemic antitumor immune response; in other cases, the viral vector is designed to be both an oncolytic virus (directly killing cancer cells) and a tumor vaccine (priming an immune response against encoded tumor antigens).
Administration of CGT products in clinical trials may be relatively simple, as for some cancer vaccines, or more complex, as for autologous cellular therapies, or image-guided intratumoral delivery of an oncolytic virus.
Personalized Medicine
The EU’s Horizon 2020 Advisory Group defines personalized medicine as: a medical model using characterisation of individuals’ phenotypes and genotypes (e.g., molecular profiling, medical imaging, and lifestyle data) for tailoring the right therapeutic strategy for the right person at the right time. In oncology clinical trials, personalized medicine often relies on DNA sequencing to select participants for enrollment, and/or to create custom CGT products tailored to a specific participant’s tumor.
Inherited Genotypes
Sometimes CGT therapies depend on knowledge of a participant’s inherited genotype. For example, every person inherits a set of genes, encoding a family of cell surface proteins called Human Leukocyte Antigens (HLAs). Humans have three HLA Class I genes, designated A, B and C, on each copy of Chromosome 6. Each HLA gene exhibits a high level of genetic diversity in the human population, meaning that each person expresses a nearly unique combination of up to six Class I HLA forms on almost every cell in their body, including cancer cells. Each Class I HLA molecule on the cell surface presents a short peptide fragment of some antigen found inside the cell.
Every naturally occurring T cell expresses a T cell receptor (TCR) that only responds to a single type of HLA molecule. For the major class of T cells in each person, the circulating T cells are only capable of mounting a specific response to one of the six HLA molecules expressed on that person’s cells. Researchers have studied circulating blood T cells from persons who have recovered from cancer and identified T cells expressing TCRs specific for peptides derived from cancer/tumor antigens. These TCRs are the basis for some successful oncology products; however, each TCR gene product is only capable of recognizing cells expressing one specific form of Class I HLA molecule.
In August 2024, the FDA approved Tecelra (afamitresgene autoleucel) for the treatment of unresectable or metastatic synovial sarcoma. Tecelra is an IEC genetically modified to express a TCR (also known as a TCR-T) that responds to tumor antigen only in the context of specific HLA molecules (forms of HLA A*02). Therefore, Tecelra and other HLA-A*02-restricted TCR-T products are only designed for use in participants with one of the relevant HLA-A*02 genotypes, inherited from one of their parents at the HLA-A locus on Chromosome 6. Prior to enrollment in a TCR-T clinical trial, participants must undergo genetic testing to see if they meet HLA genetic inclusion criteria. For these reasons, any TCR-T clinical trial qualifies as a form of CGT personalized medicine.
Neoantigens
Aside from studying inherited genotypes, a major focus of personalized medicine in oncology is sequencing DNA derived from cancer cells themselves. As cancerous cells begin to divide out of control and grow into a tumor, the cells undergo genetic mutations, many of which promote tumor growth and help the tumor escape from natural control mechanisms. Proteins encoded by these mutations are sometimes different enough from the normal forms that the immune system can recognize them as foreign. Therefore, these new immune targets, or neoantigens, are potential targets for development of therapeutic cancer vaccines. Because of the random nature of cancer mutations, the majority of neoantigens present in a tumor are unique to that tumor and to that cancer patient. This means that in many cases, a neoantigen vaccine designed for one person is based on unique results of sequencing that person’s tumor DNA to find tumor-specific mutations.
Combining Personalized Medicine and Gene Therapy
Personalized medicine based on DNA sequencing started out as a separate research endeavor and line of inquiry from CGT. However, they have proven to be complementary, and many programs are now based on a combination of personalized medicine and ATMP. This is easily apparent in personalized neoantigen vaccines delivered in the form of nucleic acid or viral vectors. For many of these approaches, DNA is extracted from a tumor biopsy, sequenced, and analyzed for the presence of candidate tumor neoantigens. Genetic sequences encoding those participant-specific neoantigens are then incorporated into a molecular vaccine, which can be administered to the participant as an investigational therapy.
Some neoantigen vaccines are encoded in viral vector vaccines or in oncolytic viruses that serve both to kill tumor cells and to drive anti-tumor immune responses. Others are encoded in nucleic acid vaccines, such as mRNA packaged in lipid nanoparticles. For all these approaches, the therapeutic intent is to drive new immune responses to an array of antigens expressed by tumor cells.
Immune Checkpoint Inhibitors
One of the most notable successes in oncology over the past decade is the use of immune checkpoint inhibitors. T cells in different stages of activation and differentiation express inhibitory suppressors (also called checkpoints) on the cell surface—the best-known examples being cell surface receptors PD-1 and CTLA-4. Tumor cells frequently exploit these checkpoints by expressing a matching ligand (e.g., PD-L1) that puts the brakes on T cell activity. Medical interventions that block the ability of checkpoint receptors to inhibit T cells have been shown to produce significant, and sometimes dramatic clinical benefits in the form of immunotherapy. Accumulating evidence suggests that checkpoint blockade is particularly beneficial for enhancing the immune response to neoantigen cancer vaccines. As part of experimental protocols, investigational checkpoint inhibitors may be delivered as manufactured protein products/monoclonal antibodies, or as ATMP gene transfer products encoding the investigational checkpoint blockade.
Clinical Trial Challenges Involving Personalized Medicine and ATMPs
Many personalized medicine approaches and CGT modalities have been developed to treat cancer as independent stand-alone therapies. But cancer cells have the unfortunate tendency to evolve and become resistant to lines of treatment with a single mechanism of action. Therefore, many of the most promising treatment approaches are combination therapies.
Genetic Sequencing
As discussed above, more than one type of genetic sequencing is applicable in oncology clinical trials, and different uses will require different kinds of samples.
Some sequencing is intended to identify inherited genotypes that may determine whether a participant can benefit from a specific type of intervention—for example whether their cells express the appropriate HLA-A*02 subtypes to benefit from treatment with a TCR therapy like Tecelra. Chromosomal DNA for this type of analysis may be extracted from a regular blood sample or from a cheek swab.
Some sequencing is intended to analyze genotypic information from the tumor. In most cases this will involve extracting DNA from a tumor biopsy sample. Acquiring tumor tissue in the appropriate quantity and from the correct anatomic sites, with appropriate storage and shipping conditions to preserve sample quality and identity requires careful planning and quality control. Depending on the scientific goals of the study, a sufficient sample may be required to provide a single snapshot of the tumor genotype, or a cross-sectional analysis of variable DNA sequences at multiple metastatic locations, or a longitudinal analysis of sequence evolution over time. In some cases, the biopsy sample will be used not only to analyze tumor DNA but also to analyze the genetic sequences of immune cells present in the tumor (i.e., tumor infiltrating lymphocytes, or TILs). This information may be used to generate personalized TCR-based therapies, for example.
These samples may be used for clinical trial screening and enrollment, and they may also be used to manufacture a personalized medical product. Participants enrolling in these studies may have rapidly progressing late-stage cancer, such that prompt, efficient sample processing and delivery are paramount. While samples are being analyzed and therapeutics are being prepared, some participants may require bridging therapy to maximize their health and survival in the interim.
Cellular Therapies
Many of the cellular therapies mentioned above are autologous products, meaning that they must be manufactured from the participant’s own white blood cells. Precursor cells are usually extracted from an apheresis product, which is transported to a local cell therapy production center or shipped to a central manufacturing site. The procedural and regulatory requirements for production, shipping, storage, and administration of autologous cellular products are very complex. In addition, expected serious adverse events related to these therapies include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require specialized clinical knowledge and experience to manage. The Foundation for Accreditation of Cell Therapy (FACT) provides accreditation for sites that can demonstrate quality, competence, and experience in areas such as leukapheresis and IEC clinical treatments.
Biosafety Oversight
In clinical trials, biosafety refers to a combination of training, equipment, monitoring, and oversight for prevention of unintended and accidental exposure to infectious substances and gene transfer agents. Depending on the jurisdiction, various CGT products may be categorized as genetically modified organisms (GMO - a classification prevalent in the E.U.) or as human gene transfer [HGT products - a classification used by the U.S. National Institutes of Health (NIH)]. Use of GMO or HGT products in a clinical trial will often require approval by local or national biosafety oversight entities. For research subject to the U.S. NIH Guidelines for Research Involving Recombinant and Synthetic Nucleic Acid Molecules, a clinical trial protocol must be approved by an Institutional Biosafety Committee (IBC) registered with the NIH prior to initiation of the research.
As an example, a live replicating oncolytic virus expressing tumor neoantigens may be classified as Biological Safety Level 2 (BSL-2). Through collaboration with study staff and investigators a biosafety committee can establish required and recommended practices for safe shipment, storage, transport, preparation, administration, and disposal of the genetically modified material. An IBC-approved protocol should also include procedures for safe inactivation and clean-up of spills and for reporting of exposures and unexpected events.
Just-in-time Initiation
A particular challenge encountered in some personalized medicine trials is the use of DNA sequencing to identify rare or otherwise difficult to recruit participants with a particular genetic profile. This means that many clinical trial sites may be engaged to acquire DNA samples for screening purposes, but only a few sites may identify a candidate that meets all the enrollment criteria. When a candidate is identified, it may become necessary to rapidly execute site initiation requirements to enable enrollment in the treatment portion of the study. Sites engaged in this type of personalized medicine trial will need to plan for just-in-time processes allowing rapid and agile study startup on short notice.
Conclusion
Because of genetic instability, cancer cells can rapidly evolve and become resistant to established first-line therapies. An important way to fight resistance is to apply two or more approaches with orthogonal mechanisms of action to block the replication of cancer cells. Some of the most promising combination approaches involve the confluence of personalized medicine and ATMP/CGT approaches. Execution of these combination treatments requires special planning and advance expert consultation. Many sites and investigators are discovering that the extra resources required are justified by the promise of real clinical benefits for patients.
Author Bio
Daniel Kavanagh, PhD, RAC, is the Senior Scientific Advisor, Gene Therapy, Vaccines, and Biologics at WCG. Prior to joining WCG, he was Assistant Professor of Medicine and Institutional Biosafety Committee Vice Chair at Harvard Medical School, and Assistant Immunologist at the Massachusetts General Hospital. He was also co-chair of a Phase 1 clinical trial of a therapeutic mRNA vaccine. He is certified in US Regulatory Affairs (RAC) by the Regulatory Affairs Professional Society.
