Immunotherapies have led to impressive outcomes in multiple cancer types, however most patients relapse or do not initially respond, and biomarkers of resistance are needed to design rational combinations. Oncogenic programs, namely those associated with mesenchymal transformation, alter the microenvironment to promote immune evasion and therapeutic resistance. A mechanistic understanding of these pathways linked to biomarker and therapeutic development promises to usher in a new era of precision immuno-oncology.

There are many recent publications highlighting TGFb pathway activity in the context of chemo and immune therapy resistance. TGFb is a pleiotropic signaling molecule that impacts many cells within the tumor microenvironment. Several groups are moving forward with TGFb antagonists in clinical trials, but substantial clinical impact has remained elusive. I will discuss Novartis’ work on this target in preclinical models and in clinical trials: 1) What is the MoA of TGFb blockade? 2) How to assess activity of TGFb blockade in clinical trials? 3) What are potential combination partners for TGFb blockade? 4) How well do mouse models recapitulate potential clinical activity?

Syngeneic and humanized mouse models are used to evaluate efficacy and MOA of next generation I/O therapies. Ongoing work aims to build preclinical models that recapitulate the biology needed to evaluate rational combination strategies. 

Pembrolizumab-based combinations with chemotherapy and targeted agents have improved survival and other outcome measures across a broad spectrum of tumor types. We have generally taken a mechanism-agnostic approach to evaluating and progressing pembrolizumab based combinations to registration-directed development, and have pivotal studies underway with IO-IO, targeted therapy, chemotherapy, radiation, and antibody-drug conjugates. Single agent activity of pembrolizumab and the combination partner has generally been the best predictor of combination benefit.

NT-I7, a long acting IL-7, has shown promising early anti-tumor activity in two immune-cold tumor types. In MSS CRC, where pembro had 0% ORR, 3 PR/iPR were observed in 17 evaluable pts treated with NT-I7+pembro, for an iORR of 18%. Furthermore response was also observed in pancreatic cancer, where pembro also had 0% ORR, despite short follow-up. Responses, once occurred, are durable and continue to deepen over time.

Our laboratory has developed, optimized, and translated mesothelin-targeted CAR T cell therapy to patients with mesothelioma, and metastatic breast and lung cancers. We further translated strategies to overcome barriers to successfully translating CAR T cell therapy for solid tumors. One such strategy already in clinic is combination immunotherapy of CAR T cells and checkpoint blockade agents or PD1 dominant-negative receptor within the CAR T cell. These preclinical supportive rationales and clinical trial results will be presented.

Checkpoint inhibition represented the first generation of IO therapies and truly transformed cancer care; however, many patients still experience little to no benefit from these treatments. A common approach to enhancing the effects of the first generation of I/O therapies has been to add pro-inflammatory cytokine agonists. While promising, these therapies are often toxic and have not been able to replicate success in large trials. Another novel approach, however, has been to antagonize – rather than agonize – immune-suppressive cytokines. This new “food group” holds promise as a combination therapy to reverse local immune suppression in a more tolerable manner. SRF388 is a first-in-class anti-IL27 antibody which neutralizes the immune suppressive effects of this cytokine and has recently generated exciting monotherapy and combination activity across several tumor types. Studies are underway to investigate the potential of SRF388 in multiple solid tumor types including lung, liver and kidney cancer.

Combination checkpoint blockade with αPD1 and αCTLA4 (αCTLA4 doublet) has demonstrated a 58% response rate, but a 59% grade 3 or 4 toxicity. By using single-cell RNA sequencing to study the pharmacodynamic dynamic immune responses of single agent and combination checkpoint blockade, we begin to deconvolute the mechanisms behind clinical efficacy and immune toxicity.

Genprex’s Chief Medical Officer, Mark S. Berger, M.D., will be presenting on the company’s lead drug candidate, REQORSA Immunogene Therapy in combination with immune checkpoint inhibitors for non-small cell lung cancer. An overview of preclinical studies showing that REQORSA is synergistic when combined with anti-PD1 checkpoint inhibitors, including Merck’s Keytruda, will be provided, and Genprex’s clinical programs with REQORSA will be discussed.

IRE is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. Combining IRE with intratumoral Toll-like receptor-7 (TLR7) agonist (1V270) and systemic anti-programmed death-1 receptor (PD)-1 checkpoint blockade resulted in improved treatment responses. This combination also resulted in elimination of untreated concomitant distant tumors (abscopal effects), an effect not seen with IRE alone.

Acute myeloid leukemia (AML) is characterized by poor clinical outcomes. We developed a monoclonal antibody (7C6) that retains a danger signal (MICA/B) on the surface of leukemia cells, which in turn are recognized by Fc receptors and phagocytosed by macrophages. However, half of the AML patient population have leukemia cells that downregulate MICA/B through epigenetic mechanism. We also discovered that romidepsin induces MICA/B mRNA expression in human AML cells and synergizes with 7C6 to increase expression of MICA/B protein. 7C6+romidepsin promote antibody-dependent phagocytosis and inhibit AML in preclinical models. Therefore, 7C6+romidepsin have immunotherapeutic potential.

Many companies are looking at combinations as a way to improve the performance of IO treatments, and often this requires working with another company for a given combination. This panel will examine some of the different approaches and strategies that companies have taken when it comes to selecting which types of treatments and which partners they pursue. A better understanding of priorities and preferences from one company to another can result in a better fit and success when tackling the challenge of developing combination IO therapies.

RP2 is a novel, enhanced-potency oncolytic HSV1 which expresses GM-CSF, an anti-CTLA-4 antibody-like molecule and the fusogenic gibbon ape leukemia virus membrane R-glycoprotein (GALV-GP R-). RP2 is in clinical development in a range of solid tumors alone and with nivolumab (nivo). RP2 + nivo has resulted in deep and durable responses in patients who failed prior anti-PD1 therapy (SITC 2021). Here we present biomarker data in patients treated with RP2 alone or combined with nivo from an ongoing clinical trial (NCT04336241).

I-O based therapies benefit only a minority of patients with cancer. Understanding and addressing I-O resistance presents both opportunities and challenges. While dual I-O combinations have demonstrated clinically proven benefits, some have failed. Effective I-O combinations targeting novel, complementary, or non-redundant pathways may provide synergistic treatment effects, whereas patients without pre-existing tumor immunity may benefit from I-O combination with chemotherapy or targeted therapies