The evolving immuno-oncology landscape 

Dr Ian Walters, Chief Executive Officer and Director of Portage Biotech, shares how to find the path of least resistance through the immuno-oncology landscape. 

Our bodies are naturally trained to identify and remove abnormal cells, including those that are cancerous. Under normal circumstances, a person’s immune system detects proteins on the surface of cancer cells and targets them for elimination. The main cells of the immune system that kill cancer cells include cytotoxic/killer T cells, which form part of the adaptive immune response and natural killer (NK) cells, which form part of the innate immune response¹. These cells do not work in isolation; they are stimulated by a cascade of events which may be specific to parts of cells such as specific antigens or proteins, or nonspecific defense as part of the innate immune response in macrophages, neutrophils and dendritic cells (DCs).²

So, why are some people still dying of cancer? Cancer cells can adapt and manage to find ways to evade the immune system, escape destruction and continue to grow unchecked into full tumours. Unchecked cancer growth can be attributed to inadequate, attenuated or suppressed immune response. Some tumour escape mechanisms include the expression of surface proteins to prevent cancer cells from being destroyed or the reduction of protein expression to avoid detection by circulating T cells.³ Compounding these challenges is the fact that the tumour itself can be quite complex and can constantly evolve. As cancer cells grow and progress, they modulate the environment they reside in to prevent immune cell entry and attack. This tumour microenvironment (TME) can consist of a heterogenous mix of immune cells, blood vessels, extracellular matrix and other components that support and promote cancer cell survival, progression and eventual metastasis.²

The evolution of cancer immunotherapy treatment

In the treatment of cancer, surgery, chemotherapy and radiation have long been and still remain a standard of care (SOC) for many patients in an attempt to remove and kill cancer cells from the body. However, many cancers are detected late and cannot be completely resected or treated. At the time of diagnosis, they may have already spread (metastasis). Both radiation and chemotherapy are potent killers of rapidly dividing cells, and they often kill healthy cells leading to challenging side effects. In fact, they also dampen the immune system, rendering patients more susceptible to infections and weakening the body’s attempt to mount an immune response. Often these treatments self-select for resistance cells, which then grow faster and are more difficult to treat. As a result, researchers began to look for better ways to improve cancer treatment to be more targeted, effective and preserve patient quality of life.

Finding ways to safely stimulate the immune system to attack and kill cancer is a challenge that has inspired scientists for decades. After many attempts the field has finally identified several ways to promote an anti-tumour immune response. The advantage of these treatments is they can find and remove even drug resistant cells and lead to very long-term disease control as the immune system has effectively created a vaccine response to the tumour. These types of modalities have rapidly become the SOC for many tumour types.

One of the first approaches to show promise was cytokine therapy. A class of cytokines called interleukins stimulate the growth of T and NK cells and activate the T cells to target cancer.^4,5  One of the earliest immunotherapy treatments involved the administration of interleukin 2 (IL-2), which stimulates the proliferation of T cells and its cytotoxic activity but caused severe adverse effects and toxicity due to its ubiquitous binding to receptors in healthy cells throughout the body.^5,6 For the lucky few who can tolerate these therapies, they can experience long-term benefit as the immune system will continue to fight long after the cytokine treatment has ended. This gave drug developers hope that more research could help identify safer ways to promote an anti-cancer immune response. There are a variety of companies developing next-generation cytokines that are meant to be activated in the TME and not broadly in healthy tissues. Within the next few years, Phase III trial results will be available on these approaches to confirm if they are indeed better than previous attempts.

The game changer: checkpoint inhibitors 

Over time, researchers focused on targeting more specific anti-tumour immune pathways having gained more insight into mechanisms of cancer growth and progression. In particular, the development of checkpoint inhibitors (CPI) revolutionised the immuno-oncology landscape. These therapies leveraged what’s known as the checkpoint pathway, which under normal conditions serves as the “brake” to keep T cells from attacking other healthy cells in the body and govern whether immune cells become activated or inactivated in an immune response. The pathway helps keep the immune system tightly regulated to discriminate normal “self” cells and “foreign” cells like cancer.

The idea that the inhibition of immune checkpoints could become a promising cancer therapy was first discovered in the 1990s by Dr James Allison and Dr Tasuku Honjo, eventually earning them the 2018 Nobel Prize in Physiology or Medicine. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is expressed on T cells, acts as a “brake” of immune response, downmodulating T cell activation.^7-9  Another checkpoint, Programmed Cell Death Protein 1 (PD-1), is a cell surface receptor expressed on activated T and NK cells, which interacts with PD-1’s ligand, PD-1, signaling immunosuppression and inhibiting T cell activation.^10,11 Cancer cells can evolve to co-opt these checkpoints, upregulating expression on their surface to evade immune surveillance and facilitate tumour progression.^10,11 The PD-1/PD-L1 interaction occurring within the TME can result in tumour-specific T cell exhaustion and cell death.¹¹ CPIs block this pathway and prevent tumour immune evasion, releasing the “brake” to reactivate T cells to eliminate cancer cells more effectively.

The first approved immune CPI, ipilimumab, approved in 2011, targeted CTLA-4 to treat patients with advanced melanoma.¹² Several CPIs have since been approved by the FDA, including anti-PD-1 antibodies nivolumab (Opdivo), pembrolizumab (Keytruda) and numerous others and are widely used as treatment for numerous cancer types. Typically, these work best in highly immunogenic indications like melanoma, non-small cell lung carcinoma (NSCLC) and renal carcinoma.^13,14 This is in part due to a pre-existing immune response, so just relieving the checkpoint blockade can unleash the pre-existing T cell response.

Today’s challenge: checkpoint resistance 

While CPIs are undeniably revolutionary, responses to these treatments are largely dependent on a variety of factors. About 70-80% of patients do not respond or have a limited response to CPIs. ^16,17 There are certain tumours in which CPIs have little to no benefit. Resistance is related to one of three key factors:

1. Lack of an existing immune response: Some tumours, called “cold” tumours, are poorly infiltrated by T cells.^10,18There has been extensive research into converting cold tumours into hot tumours by increasing T cell infiltration which would result in improved response to CPI therapies.¹⁵ However, an effective response requires T cells to already be mobilised against the tumour.
2. Low immunogenicity and immune recognition: Many cancers can avoid immune detection altogether by never expressing antigens on the surface of their cells that can be recognised as being sufficiently “foreign” by the immune system. Mutations in cells help the immune system recognise a cell as foreign and the type and number of mutations characterise what is called the tumour mutational burden (TMB).  The higher the TMB, the more likely a tumour will respond to CPI¹⁵.
3. A suppressive environment: Cold tumours are often associated with an immunosuppressive TME. Also referred as immune deserts, they completely lack any detectable immune cells, or sometimes the immune cells are lined up on the outside of the tumour and cannot get in (the TME cells after inhibiting their entry). In these cases, patients may either have a poor response or be completely unresponsive to CP blockade.

There is a greater need for new therapies that can selectively activate T cells against specific cancers for improved efficacy, and, more broadly, a significant need to develop approaches that improve responses to tumours that have become refractory to CPI or initiate a de novo immune response to help cancer patients achieve durable responses, increase survival and improve quality of life.

Next-generation combinations: the first step to overcoming resistance

In order to address these resistance mechanisms, scientists have been trying to combine different immunologic and non-immunologic agents to see if they can assist more patients to get into long term response. One of the first successful combinations was anti-CTLA-4 and anti-PD1 which showed additive benefit on response leading to an improvement in overall survival. This came at a significant cost with more than 50% of patients experiencing severe (> grade 3) toxicity. Since then, many CPI combinations with other CPIs have been tried without much success. Recently, the combination of PD-1 antibody with Lymphocyte Activation Gene 3 (LAG3) antibody has shown promise in melanoma.¹⁹ To address other modes of resistance, people have tried combinations with agents to support antigen recognition and immune recruitment in cold tumours. The jury is still out on many of these studies, but researchers are optimistic about seeing an improvement. Somewhat surprisingly, combinations of CPI and systemic chemotherapy have shown improvement in a variety of tumour types.²⁰ This is counterintuitive since systemic chemo also has the potential to inhibit the immune response.²¹ The challenge for the field is the complexity of the immune system with numerous cell types working in concert within complex microenvironments to prevent the immune system from attacking normal tissue. This is further complicated by overlapping pathways and feedback loops that make it unlikely that a single product or mechanism will have effects across the spectrum of cancer types and patient groups.

A novel approach to attack cancer from all sides

A new class of T cells have recently garnered attention as a potential game-changer in cancer immunotherapy. Invariant natural killer T cells (iNKTs) are a distinct class of innate-like immune cells that express the aβ T cell receptor (TCR) to recognise lipid and glycolipid antigens (CD1d) on the surface of various immune cells (e.g., DCs, B lymphocytes and macrophages) and on some cancer cells (Figure 1).^22-25 iNKTs share features of both NK cells and T cells, bridging the adaptive and innate immune system, and can secrete cytokines that kill cancer cells directly or indirectly by activating T and B cells through multiple mechanisms of action and are therefore a promising target for immunotherapy.^23,24 While iNKTs are rare, representing 0.01-1% of peripheral blood mononuclear cells, they mainly reside in tissues. They are critical components of the immune system that enable the body to recognise and attack cancer cells that otherwise contain very few immune cells and, as a result, often go undetected.²⁵ High numbers of iNKT cells in humans have been associated with improved outcomes in cancer patients’ survival, local disease control and reduced rate of metastasis. iNKTs can also correct the immunosuppressive TME by downmodulating myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs).²⁶ All of this data suggests that stimulation of iNKTs is a promising opportunity to boost immune response to cancer, both as monotherapy and in combination with other treatments, and may also address checkpoint resistance​.

Originating from the marine sponge, iNKT agonist alpha-Galactosylceramide (α-GalCer) was one of the first iNKT agonists evaluated in cancer patients but had limited clinical response when delivered.²⁷ Several groups have used α-GalCer ex vivo to activate DCs or other cell therapies. These have shown hints of improved activity, although randomised studies have not been done. The challenge with this compound is its chemistry and formulation which make it difficult to administer.²⁷ Several groups have sought to formulate next generation agents with synthetic chemistry and better formulation technology. Threitol-ceramide (ThrCer), or IMM60, is an optimised synthetic iNKT agonist that in preclinical studies demonstrated higher binding affinity to a human iNKT-cell T cell receptor than α-GalCer and resulted in extended responses both in human and mouse iNKT cells.^28,29 Compared to α‐GalCer, IMM60 was found to promote strong anti‐tumour responses and to induce a more prolonged stimulation of iNKT cells and improved potency in iNKT cell activation.^28,29

Recently, the biotechnology industry has begun to better recognize the role of iNKTs in numerous immune-related diseases and to leverage their properties for immunotherapies. One company, MiNK Therapeutics, is exploring their unmodified allogeneic iNKT cell therapy, AgenT-797, in elderly patients to treat acute respiratory distress syndrome caused by COVID-19 in patients who require mechanical ventilation. Studies show that AgenT-797 demonstrated a 77% survival rate and has also shown persistence, trafficking and anti-tumour activity in xenograft models for solid and liquid tumours.^30,31 Cancer trials are ongoing.

Appia Bio is another early-stage biotechnology company developing engineered chimeric antigen receptor (CAR)-engineered iNKT cell types from hematopoietic stem cells (HSCs) for cancer patients. With circulating iNKT numbers low in general, preclinical research in this area has explored the development of HSC-engineered iNKT cell therapy for cancer.³² Appia recently licensed its lead product to Gilead/Kite Pharma.

Kuur Therapeutics, another cell therapy company focused on iNKT cell therapies, was acquired by Athenex. Kuur’s lead programs include α-GalCer expanded DC and iNKT cell therapies. Early clinical data look encouraging. In a trial of 10 subjects with neuroblastoma (a difficult to treat brain tumour in children), two have exhibited responses with one achieving a complete response. Data to be presented later this year at the American Society of Hematology conference also show complete responses in non-Hodgkin’s lymphoma and leukemia (tumours that typically express CD1d).

How Portage Biotech is developing therapies to avoid and overcome cancer treatment resistance

Portage Biotech is leveraging its team’s longstanding experience in immuno-oncology (members have contributed to the development of several approved and in development CPIs) and treatment resistance to develop a series of novel combinations to help those not responding to the SOC. One focus is next-generation iNKT agonists. Portage’s iNKT platform includes two agonists that have advanced into the clinic, PORT-2 and PORT-3, which are designed to enable multiple parts of the immune system to attack and kill cancer. PORT-2 is a liposomal formulation of IMM60 which inserts the ceramide into the body of the liposome to improve the pharmacokinetics. PORT-3 is administered through co-delivery of IMM60 with immunogenic cancer antigen NY-ESO-1 in a Poly lactic-co-glycolic acid (PLGA) particle.³³

Portage’s strategy for stimulating multiple mechanisms that contribute to an anti-cancer response can be summarised in three steps:

1. Engaging the T cells to proliferate an inflammatory response

• • PORT-2 and PORT-3 lead to activation of the innate and adaptive immune system including NK cells, DCs, T cells, and B cells.

2. Direct the immune cells to the cancer

• • The DC activation and cytokines drive an antigen-specific CD8 T cell response and direct the immune system on what to attack.

3. Address the cancer cells’ ability to hide from the immune system

• • iNKT treatment reduces suppressive cells such as MDSCs and TAMs.

As a result of this broad immune activation, cancer cells increase the expression of lipid cell surface antigens and immunotherapy targets such as PD-L1 to convert PD-1 negative into PD-1 positive tumours, enabling the body to better recognise and fight cancer. Preclinical studies support monotherapy activity of PORT-2 in PD-1 antibody-resistant animals and suggest that PORT-2 has the ability to re-sensitise animals to CPIs. PORT-2 is currently being evaluated in a multi-arm study of a hybrid Phase I/II clinical trial in melanoma and NSCLC patients both as a monotherapy and in combination with a PD-1 blocking antibody. The aim is to show in traditionally CP responsive tumours if iNKT agonists can work as monotherapy after CPIs have failed, if the addition of an iNKT agonist will improve the outcome with a CPI, and whether iNKT agonists can reverse resistance to CPI.

Many tumours are immunologically cold and do not typically respond to CPIs. The addition of the immunologic peptides helps direct the activated DCs to mount an attack against the cancer cells. There is data that the adaptive response (i.e., antibodies and T cells) recognize tumour cells that express the immunogenic peptides, but also there is expansion of neoantigen specific cells (called epitope spreading). Data has shown that co-formulation of an iNKT agonist with tumour-specific antigens results in an up to five-fold improvement in efficacy compared to administering the two treatments separately. Published data using PORT-3 constructs suggest superior monotherapy activity compared to PD-1 in melanoma and head and neck cancer models, with additional or synergistic benefits when the co-formulation of PORT-3 is combined with a checkpoint antibody. If the initial proof-of-concept trial is successful, Portage will design additional co-formulations with other tumour-specific antigens, potentially offering a new treatment paradigm for patients with limited other options. Next-generation iNKT agonists have the unique ability to stimulate multiple anticancer immune cells, while inhibiting some of the suppressor cells. The results of the ongoing studies with Portage’s two agonists should give insights to the utility of these agents in immunogenic and non-immunogenic tumour types. Another concept is to combine next-generation agonists with cell therapies to see if that improves outcomes.

As novel immunotherapy technologies continue to emerge, there is a need to shift the paradigm in patient care by increasing response rates as well as exploring how combining these novel technologies can be used in patients who are treatment naïve (i.e., never received CPI treatment) and whose current options are limited. It has also become increasingly important to ensure all components to establish an anti-cancer response are addressed such as tumour antigen recognition, immune priming and boosting, relieving checkpoint signals and correcting the TME. The combination of all these components in each patient will hopefully allow scientists to create more effective treatments and will enable further progress in strengthening the immune system through broad reprogramming to better fight cancer.

About the author

Dr Ian Walters has over 20 years of expertise in immuno-oncology drug development. Prior to Portage, at Bristol Myers Squibb, he oversaw the international development of multiple oncology compounds, including nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4). Dr Walters received his M.D. from the Albert Einstein College of Medicine and an MBA from the Wharton School of The University of Pennsylvania. 

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