There is a major clinical unmet need for effective and safe therapies to increase progression-free and overall survival in older individuals with leukemia whose prognosis is grim. Dr. Karin Gaensler's pursuit of a therapeutic cancer vaccine continues with the development of TriLeukeVax (TLV), an engineered autologous leukemia vaccine for stimulating cytolytic immune responses to residual leukemic stem cells, to provide a new option for older patients relapsing with adult acute myelogenous leukemia—also known as acute myeloid leukemia (AML).
AML is a blood cancer in which the bone marrow makes many abnormal blood cells. There are 20,000-25,000 new AML cases annually in the US, with two-thirds of cases occurring in patients over 60.
We asked Dr. Gaensler to provide more detail about the award that has enabled her to conduct this research, and the many steps involved in pursuing FDA approval for a much needed vaccine.
Q: What is TriLeukeVax (TLV)?
A: TriLeukeVax (TLV) is a universally applicable vaccine to improve treatment outcomes for older AML patients without the risks and toxicities of transplant. Our team uses the patient’s cancer cells to create a personalized vaccine that will be given after chemotherapy to stimulate the body’s immune response to attack any residual leukemia cells the body may still harbor. Most older patients with AML have dismal outcomes due to the persistence of residual AML cells. These residual cells cause relapse, resulting in poor overall survival. To increase relapse-free survival, the patient's AML cells are engineered to express a novel combination of immune-stimulatory proteins that stimulate the patient's immune system to kill residual AML. These irradiated, engineered AML cells would be injected as a vaccine after chemotherapy.
Q: What motivated the development of TLV as a potential treatment for leukemia?
A: There is an unmet need for new and effective therapies for AML because most patients relapse and die, despite initial chemotherapy-induced remission and consolidation. This is because current treatments fail to eradicate quiescent leukemic stem cells (LSC) and AML blasts that are the source of relapse. Compelling evidence for the efficacy of immunotherapy in eliminating minimal residual disease (MRD) is demonstrated by the improved outcomes after hematopoietic stem-cell transplantation (HSCT) due to donor T cells targeting AML and LSC. While HSCT can be curative, many patients are ineligible due to advanced age, lack of a suitable donor, or extant medical comorbidities. Even after HSCT, older patients have high relapse rates and poorer outcomes due to the occurrence of more frequent high-risk sub-types of AML. In the absence of HSCT, the median survival in older patients is a dismal 15%. Thus, safer and more effective therapies are needed.
The current standard of care for patients with AML is evolving. Still, it depends on the subtype, patients' age and overall fitness, and the presence or absence of comorbidities affecting organ function. Patients with “good prognosis” AML, including those with specific mutations (chromosome 15:17 translocation, inversion of chromosome 16, or translocation between chromosomes 8 and 21), are often treated with regimens not used to treat other forms of AML and would not be eligible for TLV. For younger AML patients and some fit older patients, a 7-day regimen that includes three days of treatment with an anthracycline (daunorubicin or idarubicin), in combination with seven days of IV infusion with cytosine arabinoside (AraC) (the “7+3 regimen”) is used. Consolidation therapy with intermediate or high dose AraC for several cycles after remission induction is usually administered. This requires inpatient hospitalization. Cure rates with the 7+3 regimen are better for patients up to 60 yo. (30-45%) compared to outcomes for patients >60 yo (<10-15%). A liposomal formulation of AraC and anthracycline (Vyxeos) has shown promise in patients with secondary AML evolving after prior chemotherapy. If patients have an associated fms-like tyrosine kinase 3 (FLT3) gene mutation, then Midostaurin, an FLT3 inhibitor, is added to the regimen. Remaining older patients are often treated with a hypomethylating agent (azacytidine or decitabine) in combination with the BCL2 inhibitor Venetoclax and an FLT3 inhibitor if FLT3 mutations are present. Newer agents that target mutations in isocitrate dehydrogenase (IDH1 and IDH2) are being tested but may be less effective as single agents because resistance and immunological escape develop. In Mixed Lineage Leukemia (MLL) rearranged AML, menin inhibitors are also being tested. However, while newer agents are being evaluated, overall survival in older, transplant-ineligible patients remains poor. Novel immunotherapeutic agents are being developed for AML, particularly in the relapse/refractory setting, but remission rates have been variable, and the degree of toxicity is significant and unpredictable. This is partly attributable to AML cells' immunological escape, high-level expression of co-inhibitory ligands and low expression of co-stimulatory ligands. However, in the future, agents such as checkpoint inhibitors could be tested in combination with TLV to augment patient responses. Thus, there is also a need to characterize better the mechanisms promoting or limiting responses to immunotherapy in AML.
The goal of the TLV project is to develop an improved therapy to target both AML blasts and LSC that enables long-term eradication of AML both in transplant-ineligible patients when administered after remission induction, and in the future, in patients after HSCT, where relapse risk is 30-50%. TLV will provide a universally applicable, patient-specific therapy that could, in the future, be administered in the outpatient setting outside of major academic medical centers. The ability to administer TLV in regional centers would increase access to underserved populations in California, reducing the personal and financial costs incurred with re-location and in-patient hospitalization. If outcomes with TLV are promising, then as indicated, vaccination with TLV could also be tested as maintenance therapy in the post-transplant setting, where the risk of relapse still approaches 30-50%.
Q: Where are you in the development process of TLV?
A: Current activities include: (1) Generating three clinical scale vaccine batches meeting release criteria and completing safety studies, (2) Toxicology studies by serial vaccination of mice with a murine version of TLV and potential drug product hazard studies in immune-deficient mice, (3) Obtaining clinical Lentivirus preps with titer, identity, sterility, etc. assays completed and filing an IND with the trial design; and, beginning clinical start-up activities (by January 2025).
Q: How will the vaccine improve patient outcomes?
A: Whole-cell vaccines have advantages for stimulating AML-specific immunity: because anti-leukemic responses to whole-cell vaccines are directed to multiple leukemia-associated and minor histocompatibility antigens, some unique to the patient, risks of escape mutants due to loss of one target antigen are reduced. Although AML cells express MHC-Class-I and Class-II, as well as cell surface adhesion molecules, ligands, and co-stimulatory factors commonly expressed by professional antigen-presenting cells (APC), they are ineffective in T-cell stimulation. AML cells are potent inhibitors of T-cell activation. However, transduction of AML cells with CD80, alone or in combination with GM-CSF or IL-2, can induce leukemia-specific responses in autologous and allogeneic T and NK cells. In this context, IL-15 may be particularly synergistic with CD80 in stimulating T, NK, and NKT cell cytolytic activity. IL-15/IL-15Ra/CD80-expressing vaccines may substantially improve both the magnitude and duration of anti-tumor immunity in AML and other malignancies. In contrast to the effects of IL-2, IL- 15; a) reverses CD8+ T cell unresponsiveness to tumor-associated antigens (TAA), b) renders T effector cells resistant to suppressive Tregs, and c) has essential roles in NK and NKT cell activation, proliferation, and survival. Support for the validity of combining CD80 co-stimulation with IL-15-mediated immune stimulation is provided by studies showing that targeted T cells, expanded in the presence of CD80 and IL-15, persist and eradicate human tumors in immunodeficient mice and lyse autologous tumor cells from chronic lymphocytic leukemia patients. In our studies, the novel combination of CD80 and IL-15/IL- 15R?-mediated immune stimulation substantially enhanced anti-leukemic immunity in murine AML and patient-derived T cells after co-culture with TLV. These findings provide a compelling rationale for testing TLV in the clinical setting. Our studies build on pre-clinical and highly relevant emerging clinical trial data from King’s College London with a lentivirally engineered CD80/IL-2 transduced autologous AML cell vaccine.
Q: Will Treatment with TLV provide a universally applicable therapy for AML patients regardless of ethnicity or race?
A: Some cellular-based immunotherapies have been restricted to patients with certain HLA types (for example, HLA-A*0201, less prevalent in minority populations in the US), limiting access to treatments. The use of select HLA-restricted peptides limits the patient populations to whom the vaccine can be offered, e.g., only 30% of people who express the HLA-A2 family. This is also an issue with patient representation in donor registries for HSCT. TLV is a universally applicable, patient-specific therapy unlikely to have significant off-target toxicity. The vaccine is stable after production and cryopreservation and could be widely accessible at medical centers in California with access to blood bank irradiation facilities.
Q: What is your study design?
A: The study will be in two parts: A Phase 1 dose escalation cohort will be used to determine the Maximum Tolerated Dose (MTD) based on safety, and then a Phase 1 expansion cohort is planned to evaluate efficacy as measured by correlative immunological studies. We will apply an accelerated titration design for the Phase 1 dose escalation. The accelerated titration design treats one patient per dose level and escalates the dose for the next patient until one patient exhibits a dose-limiting toxicity (DLT) or two patients exhibit grade 2/3 toxicity during their first course of treatment. This approach offers the possibility of minimizing the time required to reach the highest vaccine dose and reducing the number of patients assigned to low doses, which are less likely to have therapeutic efficacy. It uses the first instance of first course DLT to trigger the switch as proposed by Storer20 and first grade 2/3 toxicity to provide added caution.
Q: Do preliminary studies support the project hypotheses and objectives?
A: Our view is that autologous AML vaccines expressing the synergistic combination of human IL-15, IL-15Ra, and CD80 will elicit potent anti-leukemic responses and increase relapse-free survival in AML patients after chemotherapy-induced remission. Our approach addresses the poor immunogenicity of AML cells as vaccine targets and the diminished immune responsiveness to vaccines in many patients, especially in older individuals. The primary mechanism of IL-15 activity is via trans-presentation by IL-15Ra, requiring co-expression of IL-15 and IL-15R? in the same cell. The enforced co-expression of IL-15 and IL-15Ra, the naturally occurring heterodimer, markedly increases IL-15 half-life/activity by 100-fold through IL-2/IL-15-beta-gamma-c receptors 21-23 and is an innovative feature in the design of our AML vaccine. The ability to restore immune competence, even partially, in older AML patients addresses an unmet need and could increase relapse-free survival.
Q: What value would TLV be to health care as a clinically feasible treatment?
A: The AML therapeutics market in the U.S. is estimated at US $217.3 million in 2022 (Global Newswire, May 11, 2022). The US currently accounts for a 37.19% share of the global market. Personalized cellular therapeutics have now shown efficacy, particularly chimeric antigen receptor (CAR) T cells, and have become a mainstay of therapeutics for hematological malignancies.
Q: What steps are involved in obtaining approval for TLV as a commercial product?
A: After completing the IND-enabling studies, we will finalize the clinical trial and file an IND application. Clinical trial start-up activities will be initiated with plans to proceed to a Phase 1 clinical trial with an expansion cohort. We will propose safety, toxicity, and tolerability studies with exploratory efficacy endpoints that would include the staging of the initial Phase 1 dose escalation cohort that provides for four monthly injections of TLV to determine the maximum tolerated dose (MTD) based on safety.
Then, assuming the vaccine's safety is established and no unknown toxicities are observed, we will carry out a Phase 1 expansion cohort to evaluate vaccine efficacy, as measured by correlative immunological studies. The Phase 1 trial will include transplant-ineligible patients with either primary or secondary AML who have achieved 1st or 2nd remission with chemotherapy and consolidation. The initial consent will be collecting leukemic blasts from diagnostic bone marrow for subsequent genetic modification and peripheral blood for immunological assessments. A small retention aliquot of patient AML cells will be subjected to screening transduction to determine the feasibility of generating a vaccine that meets threshold criteria (>10% of cells express CD80). Patients achieving remission (<5% blast in bone marrow) and who meet the eligibility criteria for trial entry will have consented to the Phase 1 trial. At consent, patients will typically be within 5-6 months of diagnosis and remain ambulatory. After irradiation, the Drug Product (DP) will be administered in the clinic via subcutaneous injection by nurses trained in the TLV protocol. The first cohort will use an accelerated titration design. If treatment with TLV meets all safety criteria and no adverse events are encountered, enrollment in the next cohort will be initiated. Following completion of the pivotal Phase 1 trial, or at such time as we observe signs of efficacy of the product, we will apply for a Regenerative Medicine Advanced Therapy (RMAT) designation to accelerate the development of our product to Biologics License Application (BLA) filing and licensing. Should the initial clinical data warrant, we will discuss with the FDA the option of our second trial being pivotal. In parallel, we plan to apply for orphan drug designation (ODD). A Phase 2 and Phase 3 trial would be conducted, and if successful, a BLA would be submitted for marketing approval. We will explore opportunities for commercial partnership throughout the process, particularly after the initial clinical data is available, to accelerate progress.