Over the last century researchers extensively studied immunotherapy, but repeated failures of the treatment led many to abandon it. As one scientist puts it, “The dogma at the time was, ‘Don’t even bother.’”
Fortunately, some scientists persisted, and their breakthroughs have given new hope to patients who seek out conventional medical treatment—which, as a general rule, has repeatedly failed patients with advanced cancer.
One of these immunotherapy breakthroughs harnesses the body’s own immune cells to fight late-stage cancers.
In 2015, Julia Morse, from Bath, in England, was diagnosed with malignant skin cancer (melanoma) on her cheek. Two years on it spread to the lung. A year later all treatments stopped working and her doctors started to talk about hospice.
But Julia, a retired nurse, wasn’t ready to throw in the towel. She succeeded in getting enrolled into a trial to test two new drugs. Unfortunately, the drugs couldn’t stop progression of the disease.
Even after this setback, Julia didn’t give up and was rewarded with enrollment into another trial for an immunotherapy, called tumor-infiltrating lymphocyte (TIL) therapy, in January 2020.
In less than a month, the 1½ inch tumor in her lung more than halved, and over the next year it disappeared completely. The tumor on her cheek also shrank (it is now growing again, and she is having a different treatment).
TIL is a form of immunotherapy that’s currently being put through clinical trial on patients only after an established form of immunotherapy, immune checkpoint inhibiting drugs (ICIs), has failed.
The problem with “old” immunotherapy
Unlike chemotherapy, which kills cancer cells directly, or targeted therapy, aimed at specific molecular targets within tumors, immunotherapy unleashes the body’s own T-lymphocytes – T-cells - to attack the cancer. This is something the body is often unable to do by itself.
Here’s why…
Checkpoint proteins live on the surface of T-cells and their job is to switch on when the body is confronted by an enemy. Once they receive the “on” signal, T-cells go into attack mode. When their job is done, the checkpoint proteins give the “off” signal and the T-cells return to sentinel duties.
T-cells are switched on to infiltrate and destroy tumors just as they do for pathogens, but cancer proteins can sometimes respond to this by blocking the signal, putting the brakes on the T-cells, allowing cancer cells to continue growing.
The idea of immunotherapy is to use drugs that prevent cancer cells from blocking the “on” signal, freeing T-cells to attack the tumor. The most common form of these drugs, called immune checkpoint inhibitors, are used in a wide range of cancers. However, they have proven to be very successful only in a small number of patients.
Stage IV patients had their lives extended
Dr. Padmanee Sharma, from MD Anderson Cancer Center in Texas, said, “The survival outlook for patients with metastatic bladder cancer used to be less than one year, but I’m now seeing some of my patients coming back to the clinic over and over again, five years and longer. It’s very rewarding to see that stage IV cancer patients can have hope.”
ICI treatment has proved most successful in melanoma. Patients expected to live less than a year are alive six years on and may even be cured. Unfortunately, most melanoma patients don’t respond—including Julia. For those that do, about one in five will see a complete disappearance of all visible metastases.
In 2018, the percentage of patients estimated to respond to ICIs for all applicable types of cancer was a measly 12.46 percent—I don’t like those odds! A different form of immunotherapy was needed for unresponsive patients.
That’s where this new TIL immunotherapy comes in.
How does TIL work?
Treatment begins with a biopsy or tissue taken from the patient’s primary tumor. If it’s inaccessible, then it’s taken from another tumor site. In the laboratory the most active and powerful T-cells are extracted and grown into billions with the help of growth factors.
“Not all the cells will have anti-cancer activity," explains Dr. Andrew Furness, consultant medical oncologist at The Royal Marsden Hospital, London, “but you hope amongst the billions there are some bona fide killers in high numbers."
TILs that are present in the patient's tumor are used because these lymphocytes are likely to recognize many unique targets and genetic mutations in the tumor. TILs are therefore a highly personalized form of T-cell immunotherapy.
After three weeks in the laboratory, these powered-up immune cells are drip-infused into the patient to seek out and destroy the tumors in a one-time procedure. Before the infusion, the patient receives chemotherapy to deplete the body of immune cells that would compete with the TILs, allowing them a better opportunity to grow and reproduce in the body. The hospital stay is about two weeks.
Interestingly, TILs continue to be active years after the infusion. This helps eliminate recurrences, allowing some fortunate patients to remain tumor-free for a long duration, perhaps permanently.
TIL therapy is still experimental but has been shown to be effective in trials of many different types of cancer in those who have run out of options and have a very poor prognosis. One such trial was the one Julia was enrolled in.
Melanoma response rate is 36 percent
Julia was one of 66 in the multicenter trial across the U.S. and Europe for patients with metastatic melanoma (stage IIIC or IV) where all other treatments had been exhausted and expected survival was in weeks or months.
The findings were promising.
Two patients (three percent) had a complete response (no evidence of disease) and twenty-two (33 percent) had a partial response, giving an overall response rate of 36 percent. Another twenty-nine (44 percent) had their disease stabilized to give a disease control rate (complete, partial, and stable) of 80 percent. Over half of those who responded continued to respond after 18 months follow up.
The researchers summarized by writing, “TIL cell therapy was efficacious and demonstrated durable responses in heavily pretreated patients and represents a potential new standard of care for patients with advanced melanoma following failure of ICI (immune checkpoint inhibitors) and targeted therapy.”
A case report for a patient with metastatic melanoma was presented in 2018 by immunologists in China. The patient was treated with ICIs and TILs combined. Complete remission was achieved approximately four months after the initiation of treatment and the patient was still in complete remission one year after the infusion.
Success with other cancers
Melanoma has been the most successful cancer treated because it has a very large number of mutations. The more mutations, the more targets TILs will recognize, but it can also be effective in other types.
In patients with metastatic cervical cancer, there was an overall response in five of 18 (28 percent) patients, two of which were complete and ongoing 53 and 67 months after treatment.
Tumors have also regressed in patients with bile duct and colon cancers. For breast cancer - a case report was presented in 2018.
As traditional TIL therapy was unlikely to be effective because breast cancer has very few mutations, the lymphocytes were engineered to address the four mutations in the tumor. This resulted, the authors wrote, in “the complete durable regression of metastatic breast cancer, which is now ongoing for greater than 22 months.”
Preliminary findings from the trial in which this case report was taken were released in February. Nearly four years further on, the patient remains cancer free.
Of the other five women treated, two had tumor shrinkage of 52 percent and 69 percent after six months and ten months respectively and have no evidence of cancer approximately five years and 3.5 years respectively, after their TIL treatment.
“It’s popular dogma that hormone receptor–positive breast cancers are not capable of provoking an immune response and are not susceptible to immunotherapy,” said study leader Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research.
“The findings suggest that this form of immunotherapy can be used to treat some people with metastatic breast cancer who have exhausted all other treatment options. It’s fascinating that the Achilles’ heel of these cancers can potentially be the very gene mutations that caused the cancer.”
Getting TIL therapy
Currently, taking part in a clinical trial is the only way of obtaining TIL therapy, so if anyone is in the unfortunate position Julia Morse found herself in, this avenue may be worth pursuing. Many TIL therapy trials are in progress and are currently recruiting patients with different forms of advanced cancer.
That said, I would seek out the opinion of an alternative cancer clinic doctor with success treating your type of cancer before ever considering TIL or any other conventional immunotherapy. Because, while TIL does harness your immune system to fight cancer, it does so in a way that first damages the immune system through chemotherapy. Natural immune therapies and alternative cancer-killing treatments generally don’t damage the immune system to succeed in healing cancer. And when chemotherapy is used, the drug has been tested against your cancer cells in a test tube and proven effective before being employed in very low doses. What’s more, it’s only used for the purpose of killing cancer, not knocking out your immune system.
Best regards,
Lee Euler,
Publisher
References:
- https://www.dailymail.co.uk/health/article-10561901/New-therapy-resets-bodys-defences-
attack-cancers.html - https://ascopubs.org/doi/10.1200/JCO.21.00612?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma
- https://www.mdanderson.org/cancerwise/why-doesnt-immunotherapy-work-for-
everyone.h00-159385101.html - https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2732329 Estimation of the Percentage of US Patients with Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397671/ A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers
- https://www.nature.com/articles/s41591-018-0040-8 Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer
- https://pubmed.ncbi.nlm.nih.gov/35104158/ Breast Cancers Are Immunogenic: Immunologic Analyses and a Phase II Pilot Clinical Trial Using Mutation-Reactive Autologous Lymphocytes
- https://www.nih.gov/news-events/news-releases/nih-study-advances-personalized-
immunotherapy-metastatic-breast-cancer
