ABSTRACT
Background We are developing MiNK-413;a novel allogeneic CAR-iNKT product targeting BCMA and secreting soluble IL-15 for treatment of relapsed/refractory Multiple Myeloma (rrMM). Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized treatment of rrMM with two autologous products already approved by the FDA. However, current treatments come with significant toxicity, cost, and logistical challenge and many patients relapse, with 60% of relapsed patients still expressing BCMA. To address these, we propose the use of invariant Natural Killer T (iNKT) cells as a platform for BCMA-targeted allogenic cell therapy for rrMM. iNKT cells have potent immunostimulatory activity and intrinsic CD1d-and NK receptor ligand targeted cytotoxicity, and do not cause Graft versus Host Disease due to their invariant T cell receptor. In our native iNKT cell (agenT-797) clinical trials for COVID, solid tumors and Multiple Myeloma we observe excellent tolerability to up to 1 billion cell dosing with minimal treatment-related adverse events, absence of signs of CRS or peripheral neuropathy, and early signs of biological activity. AgenT-797 is administered without prior lymphodepletion, which is an approach we intend to pursue with MiNK-413. Methods Our proprietary CARDISTM platform consists of highly diverse (>1010) scFv library screening followed by library-based direct functional selection in CAR format using mammalian display. Candidates can be further optimized using affinity tuning to ensure optimal and highly selective on-target/ on-tumor activity. We developed a manufacturing approach to engineer and specifically expand CAR and soluble IL-15-expressing allogeneic iNKT cells. Lead candidates are assessed in vitro and in vivo for cytotoxicity, cytokine secretion, exhaustion, tumor homing and persistence. Results Discovery using our CARDISTM platform generated a fully human, potent, and specific anti-BCMA CAR which forms the basis for MiNK-413. Xenograft in vivo studies demonstrate effective bone marrow homing, and potent cytotoxic activity, with soluble IL-15 prolonging persistence. In vitro data show potent immunomodulatory activity and lack of exhaustion against BCMA+ human hematologic tumor cell lines in vitro and in vivo. Conclusions Combination of our proprietary CARDISTM and iNKT platforms enabled rapid discovery and development of MiNK-413, a next generation armored allogeneic BCMA-targeting CAR therapies. MiNK-413 is eligible to target a broader rrMM patient population due to intrinsic iNKT cell properties such as effective bone-marrow homing, high BCMA specific activity augmented by natural CD1d and NK receptorligand mediated activity. We believe MiNK-413 will provide additional benefits to rrMM patients beyond currently available treatments.
ABSTRACT
Introduction: B cell maturation antigen (BCMA) is a novel target for T cell immunotherapy in MM including bispecific antibody (bsAb) and chimeric antigen receptor therapy (CAR-T). BCMA is critical for survival of the long-lived plasma cell, responsible for generation of protective antibodies. Impaired immune reconstitution, cytopenias, B cell aplasia and hypogammaglobinemia can compound preexisting MM-induced immunosuppression. In the case of bsAb, potential redirection/activation of T regulatory cells can create an immunosuppressive milieu. Herein, we describe the clinically relevant infectious complications observed across different BCMA-directed therapies used across multiple clinical trials at our center. Methods: Infections confirmed by microbiologic or histopathologic evidence were captured from the D1 C1 of bsAb and D 1 of lymphodepleting chemotherapy of autologous BCMA CAR-T therapies. The NCI CTCAE v5 was used to describe the site and grade of infections. Hypogammaglobinemia and severe hypogammaglobinemia were defined as ≤700 mg/dl and ≤400 mg /dl, respectively. Standard antimicrobial prophylaxis included herpes zoster prophylaxis for all MM patients with antibacterial (levofloxacin) / antifungal (fluconazole) during periods of neutropenia and IVIG supplementation as per the treating physician's discretion. PCP prophylaxis was prescribed to CAR T recipient per institutional guidelines. Descriptive statistics and comparisons were performed using two-sample t-test for continuous variables and chi-square goodness of fit test for categorical variables. Results: We identified 62 patients who received BCMA-directed bsAb (n=36) or CAR-T (n=26) between 2019-2021(table 1). The median age was 66 (range 48-84) years with % females and 14.8% of patients belonging to Black race. The median time to bsAb and CAR-T use from diagnosis were 6.6 (range 0.83-15.5) and 2.6 (range 0.35-14.4) years, respectively. The median lines of prior therapy were 6 (range 1-11) with BCMA CAR-T recipients receiving fewer prior lines of therapy (4 vs 6, p=<0.001). The baseline lymphocyte count was higher in the CAR-T (14.71 vs 0.84;p=<0.001). Baseline severe hypogammaglobulinemia and lymphopenia were present in 30% and 26.7% of all patients, respectively. Tocilizumab was used in 40.9% (bsAb -30.8% versus CAR-T 55.6%) patients for CRS. IVIG was used in 25% of patients. The median study duration for bsAb was 4 (range 0.03- 24) months across multiple dose levels. Median follow up among CAR-T recipients was 3.9 (range 0.3 - 22.3) months. Among recipients of bsAb, 41.2% of patients experienced at least one episode of infection vs. 23.1% with CAR-T (p=0.141). The cumulative incidence of infection with bsAb and CAR-T were 22 and 8, respectively. The spectrum of infections with bsAb was predominantly bacterial (64.3% While gram negative infection (Escherichia coli and Klebsiella pneumoniae bacteremia, Proteus mirabilus and Psuedomonas aeroginosa urinary tract infections) were seen in 6 patients, skin infection including cellulitis occurred in 4 patients, with 1 case of necrotizing cellulitis. Bacteremia with rare opportunistic pathogens - Rhizobium radiobacter and recurrent Ochrobacterium anthropi were also observed . Viral infections included rhinovirus, cytomegalovirus, and parvovirus B19 reactivation, and COVID-19. About 50% of infections were ≥ grade 3 with 2 grade 5 events (Pseudomonas aeruginosa bacteremia and COVID-19). In the CAR-T group, we observed more viral infections (66.7% vs 35.7%;p=0.028) and fewer bacterial infections (33.3% vs 64.3%;p=0.028) . Common viral infections included rhinovirus, RSV, and herpes simplex virus reactivation. In this group 25% of infections were ≥grade 3. Conclusion: BCMA-targeted therapies seem to be associated with clinically significant bacterial and viral infections. Repetitive dosing with bsAb therapies could be the reason for the propensity to serious bacterial infections compared to CAR-T recipients and may need novel prophylaxis strategies. (Figure Presented).
ABSTRACT
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with non-progressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy. The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/TP53 mutation, with mutated IGVH. Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy. In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.