Personalized Immunotherapy: Adoptive Cell (TIL) Transfer

• 

Currently Incurable Scientist
hero symbol

TomBlogHeaderMy previous column from January 2016, “Personalized Immunotherapy: Therapeutic Cancer Vaccines” was Part 1 of a 2-Part series on “personalized” immunotherapies that are currently in clinical trials. As a recap, this is an entirely new model of drug therapy!

Instead of standardized identical batches of drugs being bulk manufactured, in the personalized drug model, each therapy is customized to match the specific genetics of an individual patient’s tumors.

I ended that column with “Each patient’s cancer is unique and personalized – why shouldn’t their treatment be too?” I also gave a preview of an exciting alternative experimental approach called “Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TILs)” which doses to patients living immune cells called “T-cells” to attack the tumors as living drugs.

A new paper was just published in the New England Journal of Medicine and highlighted in the New York Times and other major mass media showing the potential of this immunotherapy strategy to treat colorectal cancer (CRC) including non-MSI (MSS) CRC which has been resistant to immunotherapies! The current clinical trial that is treating MSS-CRC patients with this strategy is NCT01174121.

What is Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TILs)?

Even though the name of the technology sounds complex, don’t be scared off by the big words – I’ll walk you through the science and break this complex procedure down to its key components.

The first step is surgery to remove a tumor sample. This sample is used to genetically sequence the tumor and to identify immune cells called “Tumor-Infiltrating Lymphocytes (TILs)” within a patient’s tumor that are highly reactive against specific mutations found only within the tumor’s genome. These mutations are not found in the patient’s normal DNA, thus achieving cancer treatment selectivity.

Once tumor-mutation-specific TILs are identified, they are then expanded into many billions of copies. This new batch of expanded TILs = “the drug.” In this case, we are not talking about an old-fashioned pill… we’re talking about a “drug” which is many billions of copies of a patient’s own tumor-recognizing immune cells!

With the billions of TILs ready for reinfusion back into the patient, previous research has shown that pre-treatment with a form of chemotherapy (Cyclophosphamide & Fludarabine) ironically depletes the immune system in such a way that allows the re-infused TILs to live and multiply to a greater extent, which increases their therapeutic potential.  Along with the infusion of the billions of TIL cells, Aldesleukin (IL-2) is given, which stimulates the immune system.  Pembrolizumab (a PD-1 inhibitor) has also been recently added to the overall treatment process in order to remove a form of immunosuppression that is often used by tumors, although the patient published yesterday did not receive it.

Overall, it is a multi-part process of:

  • Infusing the body with billions of tumor-specific immune cells
  • Dosing IL-2 to activate the immune system
  • Dosing a PD-1 inhibitor to remove immunosuppression

The process requires a 3-4 week hospital stay at the National Cancer Institute (NCI) Hospital in Bethesda, MD. There are significant side effects endured during the treatment, and risks of very serious complications exist. But… in melanoma (where this process is used clinically), some stage IV patients are cured by it – which many patients, upon consultation with their medical team, believe justifies the risks.

An Immunotherapy Strategy Targeting MSS-CRC

2016-08_celine-ryan-and-tom-marsilje
Tom and Celine (patient #4095) - whose story made national news this week!

Epithelial GI-cancers like MSS-CRC, which are more resistant to immunotherapies than melanoma, achieved their first clinical proof of concept using this treatment strategy in 2014 when a patient with cholangiocarcinoma achieved a dramatic regression in her tumors. As a follow-up, NIH scientists worked to replicate this success in patients with more common epithelial cancers, including MSS-CRC.

These efforts have now shown signs of success with the scientific publication of significant clinical efficacy in an MSS-CRC patient!

An MSS-CRC Patient Shows Immunotherapy Success

In the New England Journal of Medicine Report, six out of seven lesions in the published patient (#4095) regressed from the immunotherapy alone. The seventh lesion, which was resistant, was removed by surgery and her doctors have now proclaimed the patient as “clinically disease-free!

Targeting the KRAS-G12D Driver Mutation

tom-celine
Celine's scans showing "clinically disease-free"

Patient (#4095) had a very exciting & unique TIL isolated from her tumor for expansion! It targeted her KRAS-G12D “Driver Mutation.”

What is a “Driver Mutation” and why is this important?  It’s important because: cancer cells are not identical inside a tumor. Even if the immune system “sees” most of the tumor, parts of the tumor may escape by simply not having the mutation that is noticeable by the activated immune cells.

Driver Mutations “drive” cancer’s growth and malignancy. For this reason, they are likely to be contained in most of the cancer cells in a tumor. Although an activated immune system can achieve “bystander” cancer cell killing within the tumor, the more cells in a tumor that have the immune target, the less reliant clinical efficacy are on bystander killing. In this setting, the Driver Mutation is the Achilles Heel of the cancer. Conceptually, an activated immune cell that targets cancer’s Achilles Heel is hitting the cancer cell at exactly at its weakest spot!

In the case of the patient (#4095), targeting a common Driver Mutation (KRAS-G12D) also offers the possibility of potentially using the information obtained from this case to treat other KRAS-G12D patients via the construction of engineered T-Cells with KRAS-G12D “TCRs.”  The TIL identified in patient (#4095) is for a specific HLA-type which may limit how many other patients could potentially be directly helped via her data – but scientific follow-up is in progress!

What Happens Next?

For current CRC patients, this therapy is not easily accessible for now. The NCT01174121 trial is very small with strict selective criteria to allow patients access. However, it is laying the research groundwork for ALL of us. If the number of responders goes up (data pending), there will be expanded/additional clinical trials, at that time, which will make the therapy easier to access!

This publication is important because, for the first time, it showed as “proof of principle” that an immunotherapy can have significant clinical efficacy in at least some patients with MSS-CRC. The research does not imply that TIL therapy is the only immunotherapy that will work against MSS-CRC. Instead, it shows that there is nothing intrinsic to at least some cases of MSS-CRC that makes immunotherapy success impossible.

This treatment is highly experimental and there are a number of questions remaining including:

  • What percentage of CRC patients will respond to this strategy?
  • Was there something rare & unique about this particular patient?
  • How long will she and any other patients respond/are cures possible as are seen in some melanoma patients?
  • How can the process be made amendable to wide-spread use?

These are all big, important questions but scientists are hard at work to address each of them!

MSS-CRC immunotherapy success may be difficult… but we now know that it is not impossible. The success published about one patient may be only a first step – but it was a necessary BIG first step we have all been waiting anxiously to see!

This new success was seen in a single patient using a highly experiment therapy, opening up as many questions as it did answers. That said, even as a single person success, with this publication the potential immunotherapy future for MSS-CRC just got brighter, something we can all celebrate!

About Tom

Tom-marsilje-stage-iv-colon-cancer-scientist-runningpic

Dr. Tom Marsilje is a >20-year oncology research scientist with “currently incurable” stage IV non-MSI colon cancer and is a Colon Club 2016 Colondar 2.0 survivor. He also writes a personal blog on life at the intersection of being both a cancer patient and researcher “Adventures in Living Terminally Optimistic” and posts updates to Twitter @CurrentIncurSci. As mentioned in his introductory post to this column, he is a Ph.D. scientist and not a M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice.

Disclosure: Fight Colorectal Cancer has received funding from Merck, the producers of pembrolizumab – a drug mentioned in this article, in the form of unrestricted educational grants. We maintain ultimate authority over website content and the content written in this article.

2 thoughts on “Personalized Immunotherapy: Adoptive Cell (TIL) Transfer

  1. Thanks so much for this report, it gives me hope for a cure. Dec 2013 I was diagnosed with stage 4 rectal colon cancer that spread to my lymph nodes, liver, gall bladder and left lung and no chance for a cure. Maybe 24 months to live if I do radiation and chemo which I did. Because I responded to treatment so well they suggested surgery, big surgery, but a chance for a cure. We did the surgery and I was cancer free, however it has come back and am currently on chemo again and looking like the cancer has become immune to the chemo, if that is the case, I’m hoping for immune therapy. I too have written a book “Attitude Determines Altitude, Our Roller Coaster Journey Through Stage 4 Cancer” all proceeds are donated to Cancer Research in hope for a cure.

Comments are closed.