FROM JUNE 4, 2022
David A. Karnofsky Memorial Award Lecture
Immunotherapy for Melanoma: A Believer from the Beginning
Jedd Wolchok (Memorial Sloan Kettering Cancer Center) reviewed his career in research and development of immunotherapy for treating melanoma. One obstacle to the development of anti-cancer vaccines is that most cancer antigens are mostly self-antigens that are tolerated or ignored by the immune system. Dr. Wolchok utilized xenogeneic/cross-species immunization, in which a species is immunized using a homologous gene product from a different species, and antibodies developed by the immunized species cross-reacts with the gene product from both species. Genetic immunization of mice with human gp75 leads to a decrease in melanoma metastases in mice. This technology was also used to develop an anti-tyrosinase DNA vaccine for dogs with melanoma, which eventually led to the development of the first therapeutic anti-cancer vaccine approved for any species. When this concept was applied to humans with metastatic melanoma, T cell and antibody responses were short-lived. In order to address this obstacle, Dr. Wolchok worked with Drs. Jim Allison and Jeff Bluestone to develop CTLA-4 blockade to enhance tumor-specific immune responses and combining CTLA-4 blockade with xenogeneic immunization increased tumor immunity in preclinical models. This work ultimately led to the development of the immune checkpoint inhibitor ipilimumab. Treatment of patients with ipilimumab has increased long-term survival rates to approximately 20%. Additional immune checkpoint inhibitors have been developed, most of which block the PD-1 pathway. PD-1 blockade agents have been used to treat patients with ipilimumab-resistant melanoma and patients who are ipilimumab naïve, suggesting that immune checkpoint inhibitors operate on non-redundant pathways, and therapies that combine two immune checkpoint inhibitors provide clinical benefit. At the 6.5 year-follow up from the CheckMate 067 trial investigating comparing ipilimumab and nivolumab monotherapies with ipilimumab + nivolumab combination therapy, the overall response rate (ORR) for ipilimumab + nivolumab is 58%, compared to 45% and 19% for nivolumab and ipilimumab monotherapies, respectively. Overall survival (OS) for the nivolumab + ipilimumab combination is 49% (median OS = 72 months), and melanoma-specific OS is 56%. The median duration of response had not been reached by the groups that received nivolumab, and no new safety signals or treatment-related deaths were reported. Supplementing immune checkpoint inhibitors with engineered T cells or ex vivo expanded tumor infiltrating lymphocytes are two potential methods to further disinhibit the anti-cancer immune response for patients who do not respond to immune checkpoint inhibitor therapy. Recent work from Dr. Wolchok’s lab has used targeted immunotherapies to mobilize the endogenous immune system to destroy heterogenous tumors. Previous studies have shown that a triple combination of chemotherapy (cyclophosphamide; CTX) with immune checkpoint inhibitors (anti-OX40 or ant-CTLA4 monoclonal antibodies) and adoptive cellular therapy (CD4+ T cells targeting the melanoma antigen Trp1) are highly effective at reducing advanced melanoma tumors in mice. This triple combination therapy is effective at destroying mixed tumors containing Trp1+ and Trp1- melanoma tumors in mice, suggesting immune cells are being activated to destroy Trp1- (bystander) cancer cells in heterogeneous tumors. This response is not dependent on adaptive immune responses, suggesting that the innate immune system performs bystander killing. Immunohistochemistry studies have shown that activated neutrophils are recruited to heterogeneous tumors after administration of triple combination therapy. Treatment with the neutrophil-targeting antibodies abrogates the therapeutic effects of triple combination therapy, and inhibition of other innate immune cells does not affect bystander killing, suggesting that neutrophils carry out most of the destruction of the bystander tumor cells. These data have led to the development of a working model in which tumor-specific T cells combined with immune checkpoint blockade and chemotherapy produces more active T cells, which secrete cytokines and chemokines to recruit neutrophils to the tumor. Studies to identify the specific types of neutrophils that perform bystander killing are ongoing.
Safety and efficacy of an engineered IL-2R cytokine as monotherapy and in combination with immune checkpoint blockade
- Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1.
Ulka N. Vaishampayan (University of Michigan Cancer Center) reported on ARTISTRY-1, a phase 1/2 clinical trial investigating the safety and efficacy of nemvaleukin alone and in combination with pembrolizumab against advanced solid tumors. Nemvaleukin is a novel, engineered cytokine that binds selectively to the intermediate-affinity IL-2 receptor (IL-2R) to activate CD8+ T cells and NK cells. Lack of binding to the high-affinity IL-2R mitigates toxicities associated with the high-affinity receptor. Pharmacokinetic studies showed that nemvaleukin activates NK cells and CD8+ T cells and has minimal effect on accumulation of regulatory T cells. The dose escalation phase (Part A; n=46) of the study established the recommended phase 2 dose for nemvaleukin as 6 micrograms/kg. Maximum tolerated dose was not reached with the highest dose tested at 10 micrograms/kg. Patients in Part B received nemvaleukin monotherapy for melanoma (n=47) or renal cell carcinoma (RCC; n=27), and patients in Part C (n=162) received nemvaleukin combined with pembrolizumab for a variety of advanced solid tumors. Patients in part B received a median of 3 prior lines of therapy for melanoma and 2 prior lines for RCC, and patients in Part C received a median of 3 prior lines of therapy. The monotherapy (Part B) safety profile was similar to the combination therapy (Part C) safety profile, and treatment-related adverse events (TRAEs) led to discontinuation of 3% of patients in Part B and 4% of patients in Part C. For patients with melanoma receiving nemvaleukin monotherapy, the objective response rate (ORR) was 13.0% (n=6), the disease control rate (DCR) was 80.4% (n=37), and the median duration of response (DOR) was 8.1 weeks. In the subgroup of patients with mucosal melanoma (n=6), 2 patients achieved a partial response, and 4 patients achieved disease control. Median DOR has not yet been reached. One mucosal melanoma responder has been receiving treatment for over two years. For patients with RCC receiving nemvaleukin monotherapy, ORR was 18.2% (n=4), DCR was 63.6% (n=14), and the median DOR was 15.6 weeks. All patients with RCC had received a prior line of immune checkpoint inhibitor therapy and progressed. In the combination arm (Part C), the ORR was 16.1% (n=22), DCR was 59.9% (n=82), and median DOR was 23.2 weeks. The median DOR was consistent for PD-(L)1 unapproved patients (27.6 weeks), and for PD(L)-1 approved patients who were PD(L)-1 naïve (26.1 weeks). Median DOR for PD(L)-1 approved patients who had received prior PD(L)-1 treatment has not yet been determined. Patients in Group C with platinum-resistant ovarian cancer (PROC; n=14) had an ORR of 28.6% (2 patients with complete responses and 2 patients with partial responses), DCR of 71.4%, and median DOR of 53.4 weeks. This study indicates that nemvaleukin monotherapy produces durable anti-tumor activity against melanoma and RCC, and nemvaleukin combination therapy with pembrolizumab also provides durable results against a variety of solid tumors, most notably ovarian cancers. These data support ongoing studies of nemvaleukin monotherapy against mucosal and cutaneous melanoma (ARTISTRY-6) and nemvaleukin + pembrolizumab combination therapy against PROC (ARTISTRY-7).
Safety of IL-27 blockade as monotherapy and in combination with pembrolizumab against advanced solid tumors
- First-in-human study of SRF388, a first-in-class IL-27 targeting antibody, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.
Aung Naing (The University of Texas MD Anderson Cancer Center) reported on a phase I study of SRF388, a fully human IgG1 blocking antibody to IL-27 to inhibit the immunoregulatory properties of IL-27 and to promote immune activation, especially in the tumor microenvironment. Safety, tolerability, pharmacokinetic, and preliminary efficiency studies as part of the dose escalation study (n=29) indicated 10 mg/kg as the recommended phase 2 dose. SRF388 is given IV every 4 weeks as a monotherapy and every 3 weeks with pembrolizumab. Patients in the SRF388 monotherapy and combination therapy (SRF388 + pembrolizumab) arms of the trial had hepatocellular carcinoma (HCC) clear cell renal cell carcinoma (ccRCC), or non-small cell lung cancer. Most patients enrolled in the study had received 3 or more prior lines of treatment, and most had received anti PD-(L)1 therapy as a prior line of treatment. Treatment-related adverse events (TRAEs) occurred in 21% of patients, all were low-grade, and the majority of TEAEs were consistent with advanced disease. No dose-limiting toxicities or grade 3+ TEAEs were observed. For patients receiving SRF388 monotherapy in the dose escalation study (n=27), 3 partial responses were achieved, and 11 patients achieved a response or stable disease. 64% of responders had durable disease control for 6 months or longer, and the disease control rate (DCR) was 31%. For patients with ccRCC receiving SRF388 monotherapy in the dose escalation study (n=7), DCR was 57% and 43% of patients experienced stable disease for more than 20 weeks. For patients with ccRCC receiving SRF388 monotherapy during dose expansion (n=13), there was one confirmed durable partial response in a patient with anti-PD-1-refractory disease. The DCR was 31%. For the SRF388 monotherapy cohort with HCC (n=17), no partial responses were observed. One partial response was confirmed in the combination therapy cohort with HCC, and the DCR was 67%. For HCC patients receiving combination therapy of SRF388 + pembrolizumab (n=9), the disease control rate was 67%. One immunotherapy-naïve HCC patient achieved a partial response. Pharmacodynamic studies indicate that SRF388 inhibits IL-27-induced pSTAT1 signaling in T cells, increases IL-27 levels, and upregulates expression of IFN gamma. These data indicate SRF388 monotherapy has a favorable safety profile and meets the criteria to expand the study of monotherapy for RCC to Stage 2 (additional 23 patients). SRF388 combination therapy with pembrolizumab has a similar favorable safety profile, and preliminary results justify further evaluation of its potential to complement PD-(L)1 blockade therapies.
Evaluation of an IL-2/IL-15 fusion protein as monotherapy and in combination with pembrolizumab for advanced solid tumors
- Interim safety and efficacy results from AURELIO-03: A phase 1 dose escalation study of the IL-2/IL-15 receptor βγ superagonist SOT101 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors.
Elena Garralda (Vall d'Hebron Institute of Oncology (VHIO)) reported results from a phase I study of SOT101 (SO-C101), a fusion protein of IL-15 and the IL-15 receptor alpha sushi+ domain, as monotherapy and in combination with pembrolizumab against advanced solid tumors. Preclinical models have validated synergistic effects of SOT101 and an anti-programmed cell death protein 1 antibody on anti-tumor activity and immunologic memory in mouse tumor models. In this study, 30 patients received SOT101 monotherapy (Part A), and 21 received combination of SOT101 with pembrolizumab (Part B). Dose escalation for both parts followed a 3+3 dose escalation design and designated the recommended phase 2 dose as 12 micrograms/kg. SOT101 is administered subcutaneously on days 1, 2, 8, and 9, with or without pembrolizumab every 3 weeks. 19 patients in Part A (63.3%) and 12 patients in Part B (57.1%) had received immune checkpoint inhibitors (ICIs) as prior lines of therapy. Most treatment-emergent adverse events (TEAEs) were transient and <= grade 2. The observed clinical benefit rate for patients in Part A was 61.5% (8/13). One patient exhibited a partial response for a duration > 22 weeks, and 11 patients had stable disease, which lasted 33 – 183 days. Median duration on treatment was 84 days (range 43 – 183 days), and mediation duration of clinical benefit was 190 days. The observed clinical benefit rate for patients in Part B was 78.9% (15/19); a complete response was observed in one mesothelioma patient who was ICI-naïve, and treatment for this patient is ongoing. 3 patients (2 previously receiving ICI) had confirmed PRs, ranging from 51-232 days, 2 patients have ongoing PR, and 1 patient discontinued treatment during the PR. Median duration on combination therapy was 113 days (range 7 – 429 days), and the preliminary median duration of clinical benefit was 131 days. The safety profile for SOT101 as monotherapy and in combination with pembrolizumab is favorable. The anti-tumor activity of SOT101 is promising, both as monotherapy and in combination with pembrolizumab for patients who are ICI naïve and for patients who have relapsed with ICIs. The preliminary efficacy of SOT101 monotherapy is being further evaluated in an ongoing extension in skin squamous cell carcinoma, melanoma, and renal cell cancer. Efficacy results for combination therapy in a heavily pre-treated population will be further investigated in AURELIO-04.
Safety and preliminary anti-tumor activity of a TIM-3 checkpoint inhibitor as monotherapy and in combination with PD-1 inhibitors
- Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).
Gerald Steven Falchook (Sarah Cannon Research Institute at HealthONE) presented results from the phase 1/2 AMBER clinical trial evaluating cobolimab, a monoclonal antibody against the immune checkpoint receptor, TIM-3, as monotherapy and in combination with the PD-1 inhibitors nivolumab or dostarlimab in patients with advanced solid tumors. 104 patients participated in the study. Patients in Part 1A (n=46) received cobolimab monotherapy, with non-small cell lung cancer (NSCLC) and melanoma being the most common cancers in this group. Patients in Part 1B (n=7) received cobolimab + nivolumab, with NSCLC being the most common cancer. Patients in Part 1C (n=51) received cobolimab + dostarlimab, with NSCLC, melanoma, and peritoneal mesothelioma were most commonly represented. 4 patients from 1A crossed over to 1C. Treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C) of patients, with grade >=3 events occurring in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no grade 5 TR-TEAEs or TR-TEAEs causing dose delays. Dose-limiting toxicities (DLTs) occurred in 3.0% (1/33) (1A), 40.0% (2/5) (1B), and 0% (1C) of patients.Part 1B was discontinued due to DLTs and toxicity. Objective response rates were 0% (1A), 42.9% (1B), and 16.4% (1C). Disease control rates were 13.0% (1A), 42.9% (1B), and 45.5% (1C). 3/7 patients in Part 1B achieved partial responses: two patients were anti-PD(L)-1 naïve (cervical cancer and NSCLC), and one NSCLC patient was anti-PD-(L)1 experienced. A total of 9 patients in Part 1C exhibited partial responses: melanoma (n=6), mesothelioma (n=2), and neuroendocrine carcinoma (n=1). All responding patients in Part 1C were anti-PD-(L)1-naïve. Preliminary results indicate that cobolimab is tolerated as monotherapy and in combination with dostarlimab and exhibits anti-tumor activity. A phase 2 investigation comparing cobolimab + dostarlimab + chemotherapy vs. dostarlimab + chemotherapy vs. chemotherapy alone in NSCLC (COSTAR: NCT04655976) are ongoing.
Safety and preliminary anti-tumor activity of a small molecule inhibitor of SUMOlyation in combination with anti-PD1 therapy
2506. A phase 1b, multicenter, dose-escalation study of subasumstat (TAK-981) in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Sanjay Goel (Rutgers Robert Wood Johnson Medical School) presented data from the Phase 1b dose escalation phase of a phase 1/2 study of subasumstat with pembrolizumab in patients with relapsed/refractory non-squamous non-small-cell lung cancer (NSCLC) or microsatellite-stable colorectal cancer (MSS-CRC). Subasumstat is a small molecule inhibitor of SUMOylation, and previous studies have shown subasumstat promotes anti-tumor responses alone and in combination with pembrolizumab through T cell activation and proliferation in mouse models. Patients received escalating doses of subasumstat in 3 schedules with pembrolizumab 200 mg every 3 weeks for two years or until disease progression or unacceptable toxicity. 43 patients received at least one dose of subasumstat. 35 patients had MSS-CRC and 8 had NSCLC. Serious adverse events (AEs) occurred in 42% (n=18) of patients, with one patient that experienced a subasumstat-related serious AE. Subasumstat inhibited SUMOylation and increased activation of the IFN-1 pathway in peripheral blood, increased levels of plasma cytokines, and increased NK and CD8 T-cell activation. Dose-limiting toxicities were observed in 2 (6%) patients. 6 (14%) patients required modified dosing of subasumstat, due to subasumstat-related AEs, 5 (12%) patients required dose reduction, and 2 (5%) patients were withdrawn from the trial due to toxicity. 5 patients with MSS-CRC and 1 patient with NSCLC exhibited partial responses, and treatment is ongoing for two of these patients. These results indicate that subasumstat plus pembrolizumab has a favorable safety profile and promising anti-tumor activity in patients who have received previous treatment for MSS-CRC and NSCLC. The combination therapy is currently in phase 2 clinical development. Subasumstat is also being investigated in combination with anti-CD38 antibodies in relapsed/refractory multiple myeloma and in combination with rituximab in CD20+ relapsed/refractory non-Hodgkin lymphoma.