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Adding interventional oncology to immuno-oncology

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Recent advances in cancer immunotherapy have led to an explosion of interest in the field. Commentators have described it as a revolution in the treatment of cancer and some even see it as possibly offering a cure for a portion of cancer patients [1]. Although using the immune system to fight disease is not a new concept, the excitement has been driven by regulatory approvals of monoclonal antibodies against immune system checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death ligand 1 (PD-L1) and its receptor (PD-1) [2,3]. Soon we will also have data about chimeric antigen receptor T cells (CAR-T) [4]. While very exciting, none of these therapies on its own can offer a silver bullet.

These new agents have only been shown to be effective in certain tumour types, such as melanoma, renal cell carcinoma and non-small cell lung cancer. Even in these indications, many patients treated with checkpoint inhibitors do not respond to monotherapy [5]. These therapies are also associated with immune-related side effects which differ from the known toxicities of traditional chemotherapy, further complicating their use [6,7].

It is now thought that immunotherapy will need to be used in combination with other agents or therapies to expand the proportion of cancer patients who could benefit [8,9]. Researchers are therefore turning their attention to combining different checkpoint inhibitors, or combining checkpoint inhibitors with other cancer treatments, like radiation therapy [10].

Jump-starting the immune system

Combining immuno-oncology therapies with image-guided, minimally invasive therapies is one approach that is starting to attract interest from oncology physicians.

Sometimes called loco-regional therapies, these procedures deliver a treatment precisely where it’s needed, aiming to destroy tumour cells without causing damage to healthy tissue. For example, Interventional Radiologists may insert a cryoprobe directly into an area to destroy a tumour with freezing, use beads to embolise specific blood vessels that feed a tumour, or use radioactive microspheres to give a localised dose of radiation to a tumour.

Some research data suggest there could be a synergistic effect between immunotherapy and these minimally invasive procedures [11]. A number of clinical trials are already underway to study the safety and effectiveness of immune checkpoint inhibitors in combination with loco-regional therapies.

Tumours use a variety of mechanisms to suppress the patient’s immune system and evade attack from T cells (a type of white blood cell). The goal of checkpoint inhibitors is to take the brakes off the cancer-immunity cycle by turning off signals that can inhibit the ability of T cells to kill cancer cells. But some tumours are more immunogenic than others, and other factors in the local tumour microenvironment may affect whether or not a patient will respond to treatment with a checkpoint inhibitor [12].

How could using loco-regional therapies help? First, these therapies de-bulk the tumour, which makes it easier for the immune system to tackle what remains. Second, there is also evidence that some loco-regional therapies may induce a tumour-specific immune response, or in situ vaccination, by releasing tumour antigens. Further evidence indicates they induce cytokine production, stimulating the immune system and helping to create an anti-tumour microenvironment.i If combined with a checkpoint inhibitor, these effects could enhance overall outcomes [13,14]. There is even the possibility that tumour types that do not respond to checkpoint inhibitors – so called “cold tumours” – could “turn hot” after treatment with loco-regional therapies, perhaps helping make immunotherapy more successful for a broader patient population [15].

Safety and cost are also important considerations when selecting an agent or treatment to combine with checkpoint inhibitors that are known to have immune-mediated side effects and are relatively expensive [16]. As loco-regional therapies are generally well tolerated, combining them with a checkpoint inhibitor is unlikely to substantially add to the side-effect burden and their cost-effectiveness may ease adoption of this combination approach [17].

Multidisciplinary approach

BTG is a leader in interventional oncology therapies with a growing portfolio of minimally invasive therapies used by Interventional Radiologists across a variety of tumour types, including tumours in the liver and kidney. The therapies represent different modalities that could potentially have a synergistic effect if used in combination with immune checkpoint inhibitors.

For example, our bead products block the arteries that feed liver and other hypervascularised tumours, depriving them of blood and nutrients, while our selective internal radiotherapy product delivers radiation directly to liver tumours. Our market-leading cryoablation solutions use ultra-thin needles cooled to extremely low temperatures to freeze and destroy diseased cells in bone and soft tissue, kidney, liver, lung and prostate.

While the potential for using loco-regional therapies in combination with immunotherapy shows promise, many questions remain unanswered. Today BTG has announced a partnership with the Society of Interventional Oncology (SIO), organisers of the annual WCIO conference, to fund new research in this area. Under the agreement, a working group will develop a white paper to direct research of loco-regional therapies alongside immuno-therapies, and SIO will award research grants to investigators advancing science in this area.

The complexities of manipulating the cancer-immunity cycle to fight tumours demand a multidisciplinary approach. By bringing together oncologists, immunologists and Interventional Radiologists, the partnership with SIO is fostering a collaborative environment across disciplines, which will be key to making progress as we explore these new combinations.

Image-guided, minimally invasive therapies already bring many benefits to physicians and their patients, and their use as a treatment approach for cancer is growing. We’re hopeful that by better understanding the science of how these loco-regional therapies could work in combination with immuno-oncology agents, we can help expand the number of cancer patients who might benefit from the immuno-oncology revolution.

Melanie Lee, PhD, CBE, FMedSci, DSc (Hons), is the Chief Scientific Officer of BTG

References

  1. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. doi: 10.1038/nrclinonc.2016.211 (2017).
  2. Mahoney KM, Freeman GJ, McDermott DF. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clinical Therapeutics. 37(4),764–-782 (2015).
  3. Alexander W. The Checkpoint Immunotherapy Revolution. P T. 41(3), 185–191 (2016).
  4. Zhang Q, Zhang Z, Peng M, Fu S, Xue Z, Zhang R. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside. Oncoimmunology. Oct 28;5(12):e1251539 (2016).
  5. Chen DS,  Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature. 541, 321–330 (2017).
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  9. Hermel DJ, Ott P. Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma. Cancer Metastasis Rev. DOI:10.1007/s10555-017-9656-2 (2017).
  10. Salama AK, Postow MA, Salama JK. Irradiation and immunotherapy: From concept to the clinic. Cancer. 122(11), 1659–1671 (2016).
  11. Greten TF, Duffy AG, Korangy F. Hepatocellular carcinoma from an immunologic perspective. Clin Cancer Res.19(24), 6678–6685 (2013).
  12. Blankenstein T, Coulie PG, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer. 12(4), 307–313 (2012).
  13. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 41(6), 503–510 (2015).
  14. Ishihara D, Pop L, Takeshima T, Iyengar P, Hannan R. Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment. Cancer Immunol Immunother. 66 (3), 281–298 (2016).
  15. Demaria S, Coleman CN, Formenti SC. Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer. 2(6), 286–294 (2016).
  16. Geynisman DM1, Chien CR, Smieliauskas F, Shen C, Shih YC. Economic evaluation of therapeutic cancer vaccines and immunotherapy: a systematic review. Hum Vaccin Immunother. 10(11), 3415-3424 (2014).
  17. American College of Radiology. Interventional Radiology Resources. https://www.acr.org/Quality-Safety/Resources/Interventional-Radiology Accessed 2017 Feb 14.

 

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