Attending my first in-person oncology conference since COVID struck was a fantastic experience — ESMO Congress 2022 lived up to expectations! Over the course of the conference, listening to a diverse array of presentation across many different cancer types, a few key themes stood out for me…
- With the emergence of more treatment options, many with overlapping mechanisms of actions that have approvals across multiple lines of treatment, the choice of how best to sequence treatments is a recurring question across cancer types (e.g., in breast cancer, prostate cancer, and NSCLC to name a few). At HRW, we also hear from our primary market research, that HCPs struggle with the lack of clear guidance on the optimal sequence of treatments, a concern that impacts treatment choice
- Antibody drug conjugates remain a ‘hot topic’ in oncology and are expected to further evolve with developments offering improvements across the targeted component, linker, and the payload
- Targeted therapy remains a cornerstone treatment option for many cancer types, with new targets being identified that are further segmenting patients or ‘slicing the pie’. While HCPs are being encouraged to gather the full repertoire of genetic information available, there are questions over how best to utilise this wealth of knowledge in treatment decisions
- The reach of immunotherapy continues to expand in oncology, into new cancer types, into earlier settings and in new combinations, and remains firmly a therapy class of high interest, although benefits are becoming somewhat more incremental as the class is now being explored in ‘less immunogenic’ cancers
- Tumour infiltrating lymphocytes (TILs), a type of adoptive T-cell therapy and subcategory of immunotherapy, is making a resurgence…
It is the last of these themes listed that the remainder of this blog will expand upon: The resurgence of TILs…
To put this theme into context, the first question to answer is, what are tumour infiltrating lymphocytes or TILs? Lymphocytes, either T-cells or B-cells, are a type of white blood cell that play an important role in the immune system. As tumours grow, lymphocytes recognize these cancer cells as abnormal and penetrate into the tumour in an attempt to kill the cells—these are tumour-infiltrating lymphocytes, or TILs.
In TIL therapy, the TILs are harvested from the tumour, cultured in vitro, and then infused back into the patient in combination with interleukin‐2 (IL‐2), a T-cell growth factor that drives TIL expansion, but which is also associated with side effects such as nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Prior to infusion of the TILs, patients receive a lymphodepletion regimen to remove non-tumour specific immune cells to optimize the expansion, persistence and activity of the infused TILs.
But TIL therapy is not a new idea. First evidence for clinical activity of TIL treatment for cancer came in the early 1990s, in metastatic melanoma patients treated with TILs and IL-2.1 However, the role of TIL therapy as a cancer treatment has not been established (no approval to date) with TIL therapy taking somewhat of a back seat as the development and subsequent approval of CAR T-cell therapy for haematological malignancies, has taken the ‘T-cell therapy’ limelight.
CAR T-cell therapy, in which T-cells are taken from a patient’s blood are modified to express a chimeric antigen receptor (CAR) that targets the T-cells to cancer cells – has resulted in profound clinical activity in blood cancers. However, it has not been possible to replicate this level of activity of CAR T-cells in solid tumours, in part due to the heterogeneity seen in solid tumours, where some tumour cells express the targeted antigen (recognised by the CAR-T-cells), and some do not. Given that TILs come directly from the tumour, and they recognise multiple antigens on the tumour cells already, this means they do not need to be modified, unlike in CAR T-cell therapy, and they are better placed to overcome the heterogeneity seen in solid tumours as they are not relying on a single tumour antigen.
As presented by Dr Sergio Quezada, in the ‘ESMO meets pharma: Next frontiers in drug discoveries’ special session 2, the ideal tumour target for immunotherapy (such as TIL therapy) should 1) Be recognised as foreign by the immune system; 2) Be present only on tumour cells and not healthy tissue; and 3) Be present on all tumour cells. One particular challenge faced by TIL therapy is that tumour cells are constantly evolving and acquiring new mutations and antigens. Expanding subsets of TILs that recognise only newly acquired (or subclonal) tumour antigens, that are not present on all tumour cells, will result in a lower tumour response.2
With tumour neoantigen clonality in mind, T-cells that target clonal neoantigens, which are a result of original clonal mutations formed early in tumour development, that are present on all tumour cells, are an attractive proposition – with greater TIL recognition a greater tumour response will be seen. Dr Quezada went on to discuss a new technology whereby selective expansion of TILs targeting clonal neoantigens, as identified through genomic analysis of the patient’s tumour, could result in a more effective TIL product. In addition to superior efficacy, selective expansion of clonal-neoantigen specific T-cells, would require a lower lymphodepleting regimen and a lower IL-2 dose, thereby reducing TIL/IL-2-associated toxicities.
The potential of TILs to treat solid tumours was also discussed in a Keynote lecture, which although had been planned to discuss both ADCs and cell-based therapies, was dedicated solely to TILs as an attractive therapy area. 3 During the Keynote lecture, impressive and striking images of complete tumour responses in melanoma in response to TIL therapy were shown. However, the crowning moment for TILs at this year’s ESMO conference, was the presentation of LBA3 in the first Presidential Symposium, ‘Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial’.4
The Phase III trial (NCT02278887) was an academic-sponsored trial, which randomised unresectable stage IIIC-IV melanoma patients (n=168) 1:1 to either TIL treatment (non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of TILs and IL-2) or ipilimumab (maximum of 4 doses), following progression after a maximum of one line of systemic treatment. The trial met its primary endpoint of PFS, with a mPFS of 7.2 months in the TIL-treated patient group vs 3.1 months in the ipilimumab group (p < 0.001), with a PFS benefit seen across all subgroups analysed, including patients that had received prior anti-PD-1 therapy (representing 87% of TIL-treated patient group). TIL treatment also demonstrated an improvement in tumour response, with an ORR of 41% vs 18% for ipilimumab, a trend for improvement in OS, and an improvement in health-related quality of life scores.
Overall, the data demonstrate a significant efficacy benefit of TIL treatment over ipilimumab in patients with advanced melanoma who are refractory to anti-PD-1 treatment. A key question is whether TIL therapy is superior to ipilimumab in combination with nivolumab, a combination that has since become the standard of care for advanced melanoma since initiation of the trial, (the trial took 7 years to complete). However, the results have undoubtedly provided evidence for the clinical value of TIL therapy.
We heard during the conference about approaches being considered to optimise TIL therapy, such as the selective expansion of T-cells with high tumour recognition, genetically modifying the TILs to further boost their response, and the use of ‘designer cytokines’ that specifically target TILs. We have seen from the introduction of CAR T-cell therapy into the oncology market, that the logistics of the process coupled with the manufacturing time of the cells, can represent a barrier to uptake. Therefore, it will also be important that the TIL process is streamlined and simplified for TIL therapy to fulfil its potential – we look forward to hearing more about the developments in next generation TIL therapy and are excited to hear what HCPs are saying about TILs in the near future!
By Gemma McConnell
- Rosenberg SA, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994.
- Sergio Quezada. Cell therapy: Targeting clonal antigen. ESMO meets pharma: Next frontiers in drug discoveries. Special Session, Mon 12.09.2022.
- John B. Haanen and Ton N. Schumacher. Antigen-focused, biotech-empowered: The promise of antibody and cell-based therapies in cancer. Keynote lecture. Sun 11.09.2022
- John B. Haanen. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. Presidential Symposium I. Saturday 10.09.2022