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Tumor Infiltrating Lymphocytes (TILs): Old news or the next big thing in cell therapy?

By Chantale Bernatchez, Head of Process Development, CTMC



After decades in the research space, TILs are ready to shine

Cell therapies have revolutionised the precision oncology space for blood cancers since the publication of the first positive CAR-T cell clinical trial results in 2011.

However, nearly thirty years passed between the earliest research on CAR-Ts and the first FDA-approved CAR-T therapy, as groups worked to optimise their therapeutic safety and efficacy, while navigating a complicated manufacturing process.

Unlike checkpoint blockades (the other mainstream cancer immunotherapy), which rely on the well-established, scalable generation and purification of recombinant antibodies, effective cell therapies rely on a much more complicated biological player: the cells themselves.

Developing manufacturing protocols and infrastructure to guarantee the viability of CAR-T cells throughout the journey from patient isolation, through genetic engineering, and back into the patient, was a significant hurdle to commercialisation.

However, innovations in cell processing, storage, and reinfusion brought these cell therapies from the bench to industrial scale production.

Once Novartis gained regulatory approval for their Kymriah CAR-T cell therapy in 2017, the precedent was set for other CAR-T cell manufacturers to follow suit.

While CAR-T cell therapies are revolutionary, they have been fundamentally limited to targeting blood cancers, like leukemias and lymphomas, due to a few inherent features.

Namely, there is a lack of solid tumour-specific surface antigens homogeneously expressed on tumour cells that represent good CAR targets.

Many CAR-T cells also fail to penetrate the immunosuppressive microenvironment of solid tumours.

This is a major limitation, as solid tumours comprise around 90 per cent of adult and 30 per cent of childhood cancers.

TILs: A long-awaited solution for targeting broader cancer types

Luckily, researchers don’t have to start another decades-long journey towards commercialising a solid-tumour-targeting cell therapy, as tumour-infiltrating lymphocytes have long shown therapeutic efficacy in treating advanced solid cancers like melanoma and, more recently, non-small cell lung cancer (NSCLC) in research and early clinical settings.

Unlike CAR-T cells, which retarget a diverse population of  blood T cells to potently recognise one tumour determinant, TILs represent a fraction of heterogenous lymphocytes derived directly from a patient’s tumour that recognize a broad repertoire of tumour antigens specific to the cancer they were derived from.

TILs are expanded to large numbers in the lab from small chunks of tumour tissue and re-infused into patients.

Since these cells have the natural ability to recognise tumours, they don’t require the engineered expression of antigen-targeting receptors.

TILs also have the unique capability to trace their steps back to the tumour after infusion and eliminate tumour mass.

One notable downside is that TILs experience chronic antigen exposure in the tumour microenvironment before their ex-vivo expansion, impairing their functional status. T

his may explain why effective therapeutic doses range between 20 and 150 billion cells, far exceeding the requirements for CAR-T cells, where efficacious doses range between 10 million and a few hundred million cells.

To address this limitation, several next-generation early-stage TIL therapies employ genetic engineering to boost TIL function and enhance efficacy.

Why has TIL approval lagged behind other therapies?  

 TIL therapies were demonstrating a 40-50 per cent clinical response rate in advanced melanoma patients, including a 10-20 per cent complete response rate, around the same time that CAR-T cells were garnering attention.

However, the complex manufacturing requirements and the changing treatment landscape for melanoma dampened enthusiasm for TIL commercialisation.

The FDA approval of tyrosine kinase inhibitors (BRAFi, MEKi) and the resounding success of the checkpoint blockade approach (anti-CTLA4 and anti-PD1 single antibodies approved in 2011 and 2013, respectively, and as a combination in 2015), rivaled the response rate to TIL therapy and offered more accessible and widely available manufacturing.

This raised questions around the commercial viability of TIL therapy for the treatment of melanoma.

New clinical data was needed to determine if TIL therapy could be useful as salvage therapy in patients who progressed on these new therapies.

Emerging data has now demonstrated that TIL therapy can be effective for patients who progress on checkpoint blockade, though response rates are reduced to 25-30 per cent, and the duration of response may be shorter.

TIL therapy has also shown promising early data when used alone or in combination with checkpoint blockade in several other solid tumour types, such as breast cancer, cervical cancer, and non-small cell lung cancer, for which checkpoint blockade is not as effective as a single agent, reviving interest in a more widespread application of TIL therapy.

Beyond efficacy, the complex manufacturing of TILs has made commercialisation daunting.

In particular, the high numbers of TILs required for infusion and the long manufacturing process (initially up to 8 weeks) are historical barriers.

In addition, while the inherent heterogeneity of TILs allows them to recognise an array of antigens within a solid tumour, this feature also reduces consistency from patient to patient or within a single patient.

Moreover, the lack of markers identifying potent anti-tumour TILs from bystander cells has hindered development.

Much energy is devoted to researching such markers, but none have yet been clinically validated.

Furthermore, TIL manufacturing demands more layers of coordination between the hospital and the manufacturer than CAR-T manufacturing, requiring a surgeon for tumour extraction and extra time and protocols for TIL expansion.

The adoption of TIL therapies has also been limited by the more rigorous medical steps required for their efficacy.

Compared to CAR-T cell therapies, TIL therapies require higher amounts of chemotherapy for lymphodepletion prior to TIL reinfusion and a high dose of interleukin-2 (IL-2) after TIL reinfusion.

Both steps enhance the proliferation and survival of cytotoxic TILs but come with associated toxicity risks to the patient.

Importantly IL-2 dosing can be discontinued when patients experience toxicitiy which can alleviate futher toxicity.

One distinction that must be made between the toxicity to TIL and CAR-T is that patients treated with TIL therapy do not experience Cytokine Release Syndrome (CRS) which is typically associated with CAR-T treatment.

Some on-target off-tumour TIL activity may be seen when normal melanocytes of the skin, ear, or eye are attacked producing vitiligo (discoloration of the skin), earing impairment, or blurred vision.

This collateral damage can mostly be reversed by application of local steroids in the case of hearing and vision issues.

The landscape of toxicity risks is likely to evolve as further clinical investigations into TILs bearing different genetic modifications to enhance potency are conducted.

Innovative manufacturing is the path forward

Initial efficacy studies show extreme promise for TILs in treating solid tumours (mainly melanoma) but only limited, well-resourced academic centres have been able to support TIL programs and manufacture TILs for research purposes.

These lab-specific processes have yet to be scaled or standardised to serve larger patient populations. Until now.

Iovance Biotherapeutics and other TIL manufacturers have developed a centralized, scalable TIL manufacturing process that meets regulatory guidelines and reliably produces effective TILs  (>90 per cent success).

These advances have recently resulted in FDA acceptance of the first biologics license application (BLA) for TIL therapy, filed by Iovance, for their lead melanoma-targeted candidate called lifileucel.

This may represent the first TIL therapy to gain BLA approval, generating far-reaching enthusiasm within the cell therapy space.

The next step for widespread TIL adoption is to transition the manufacture of these therapies out of small-scale biopharma companies and into large-scale manufacturing facilities.

This will require partnerships between the clinics harvesting the tumour tissue, biopharma developers, and manufacturing facilities with expertise in and infrastructure for scaling up cell therapies.

The ability of manufacturers to work together with clinicians and biopharma developers to streamline logistics, comply with regulatory guidance, and ensure product quality is the key to enabling proof-of-concept studies to advance TIL technology.

Akin to historical CAR-T manufacturing, the likely FDA approval of TIL therapy by Iovance will be an important milestone that may open the floodgates for the development of more TIL therapies, including ones that may potentially be more efficacious.

Two main approaches are being tested to improve TIL potency in next-generation products: 1) selecting tumour-specific TILs to remove bystander T cells and enrich for anti-tumour activity and 2) enhancing TIL function through genetic engineering.

A growing body of evidence supports the ability of TILs to recognise mutations present in the tumour (neo-antigens) in virtually all solid tumours although at very low levels.

Companies such as Achilles Therapeutics and Turnstone Biologics aim to identify and selectively expand anti-tumour TILs.

Other companies focus on enhancing the function of the bulk TIL product, using strategies such as surface expression of growth factors like IL-15 to obsolete the need for IL-2 dosing in patients for TIL engraftment and persistence, expressing molecules to help T-cell activation, or removing elements that prevent TIL activation or function.

These approaches are aimed at increasing TIL potency and, as such, may require a lower therapeutic cell dose.

This will be a required step to reduce manufacturing complexity and cost of goods to improve commercialisation prospects for TIL therapies.

Once critical quality attributes, such as potency indicators, are defined, the manufacturing of these therapies can be streamlined even further.

Through partnering with experts in the field of cell therapy manufacturing, new TIL modalities can be rapidly and efficiently brought to patients.

 What can be learned from upcoming TIL trials and potential marketed products?

TILs represent a new frontier in cell therapy, and their efficacy and applications are likely to improve and expand as the field grows.

Ongoing and upcoming TIL studies are likely to illuminate avenues for growth, especially for enhancing the potency of TILs.

Since only a fraction of the cells isolated from a tumour may be efficient at tumour infiltration and clearance, many researchers are working to define and enrich these cell populations.

Refined potency assays will help determine which fractions of TILs are responsible for the best patient responses.

More potent TILs will hopefully alleviate the need for lymphodepletion and IL-2 treatment, lessening the toxicity burden for patients pursuing therapy.

Moreover, clinical studies testing TIL efficacy in combination with other approved immunotherapies, such as immune checkpoint inhibitors, may lead to better treatment regimens for refractory cancers.

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