Diptheria Immunotoxin Effectively Targets B-Cell Malignancies - Phase 1 trial of DT2219

[AussieNeil]

"Dr. Vallera and colleagues enrolled 25 chemo-refractory patients with previously treated pre-B acute lymphoblastic leukemia, chronic lymphocytic leukemia, or non-Hodgkin lymphoma whose tumors expressed CD19 and/or CD22. Eight patients had previously undergone unsuccessful bone marrow transplantations. Patients had a median of three prior therapies and their median age was 55 years.

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Two of the 10 patients who could be evaluated had durable objective responses, with one complete remission after two cycles of therapy.

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All patients received a single cycle of the immunotoxin therapy at varying doses between 40 and 80 µg/kg administered as four intravenous infusions for 2 hours every other day.

The most common adverse events were low albumin, weight gain, transaminitis, and fever. These events were transient and were generally grade 1 or 2 in the patients treated at higher doses (≥ 40 µg/kg per day).

Two patients had a dose-limiting toxicity with the 40- and 60-µg/kg doses.

The patient who achieved complete remission had relapsed CD19-positive, CD22-positive diffuse large B-cell lymphoma and was treated with the 60-µg/kg dose."

These were tough to treat patients.

cancernetwork.com/news/immu...

Neil

Photo: We've had some very strong winds this past year, bringing down many trees, which in turn can bring down farm fences. This tree amazingly dropped on a dropper (the steel fence post) and embedded itself sufficiently to stay stuck there when the tree was sawn up.

[HelloCLL]

Hope!

[ThreeWs]

Hi Neil,

"It's like deja vu all over again." Yogi Berra

Using bacterial toxins are not a new idea. The full history of Dr. Coley and his fight against the medical establishment and search for curing cancer is interesting. en.wikipedia.org/wiki/Coley...

WWW

[AussieNeil Partner Administrator in reply to ThreeWs]

Perhaps Dr Coley was over a century ahead of his time, considering we are only now beginning to understand the complexity of our immune system and hence how we might use our hard won knowledge to enhance its activity against cancer.

[AussieNeil Partner Administrator in reply to ThreeWs]

Coincidentally, New Scientist has just electronically republished an article from just over a year ago about research that may explain Dr Coley's positive results. It seems that T-cells may fight cancers if activated repeatedly by bacteria induced fevers: newscientist.com/article/mg...

(Free to read providing you are registered)

Neil

[cllady01 Former Volunteer in reply to AussieNeil]

Neil, does that mean the more bacterial fevers we have had in our lifetimes, T-cells have become stronger, or does it mean a way to fight cancers is to induce bacteria fevers?

I am wondering if those of us who have longer w/w times have developed T-cell strengths from some childhood and youth diseases.

[AussieNeil Partner Administrator in reply to cllady01]

Well spotted. I'd say this would be a rich area for investigation for anyone looking into alternative therapies for CLL.

Cancer cells, including CLL cells, survive the body's normal T-cell vigilance by impairing their function. CLL cells control their microenvironment in nodes and bone marrow to enhance their survival by effectively putting T-cells to sleep, which is why we are more susceptible to secondary cancers. Cancer cells are not as robust as the normal body cells; their normal function is impaired because of errors creeping in during the cloning process. That's why we often get reports of 'smudge cells' on our blood test reports. (Smudge cells are just CLL cells that have less robust cell walls than healthy B-cells and easily rupture when a blood sample is taken.) So anything that stresses our body cells may help us get the upper hand over any cancer. Chemotherapy and radiation therapy work the same way; the trick is developing a method whereby we can finely control the degree of stress placed on the body so that nearly identical healthy cells can survive with little to no damage, while the cancerous cells are fatally weakened. So to use this method, we need to develop a means of carefully inducing fevers to maximise the damage to the cancer while minimally affecting our bodies. This is not something you'd want to experiment with on your own either; don't forget that often it's our body's reaction to an illness that makes us feel so washed out and ill more so than the infection. The over-reaction of our immune system can be deadly - as was recognised with SARS deaths. It's also why neutropenic sepsis can kill us:

quora.com/What-is-a-cytokin...

This full article may explain it better: 'It’s not the pathogens that do the good work. But the way our bodies respond to the pathogens is key. Infection events, especially those that produce fever, appear to shift the innate human immune system into higher gear. That ultimately improves the performance of crucial biological machinery in the adaptive immune system. This lesson comes, partly, from doctors who risked making patients sicker to try to make them better.'

miriam-english.org/files/Ha...

The DT2219 research I originally posted about is a bioengineered 'diphtheria toxin bound to a variable fragment of antibodies targeting CD19 and CD22.' Think of it as a CAR-T therapy using the diptheria toxin instead of T-cells taken from the patient.

Neil

[cllady01 Former Volunteer in reply to AussieNeil]

Since T-cells are produced in the Thymus which normally stops production and slowly dies around puberty, it is amazing that any are still available in a 75 year old. Has there been any study relating to active Thymus production and its possible use in treatment?

I have "1.8% T cells (CD3+ which show normal expression of pan T antigens: CD 2, 3, 5, & 7 with a ratio of CD4:CD8 of 2.9 (normal 1—4)"

Does that mean anything to anyone?

My hemo/onco has not taken the time to discuss anything with me since I got copies of the FISH/Flow Cytometry/immunophenotyping.

I show IGHV for Gene 4-59 (14q32.22 and have a dual deletion of 13q14.3. I know from searching internet, that this is one of the reasons I have a 16 year non-treatment blessing.

Sorry, if this is not the place to have ask this. I get involved in an area, and relate all to my own situation.

[AussieNeil Partner Administrator in reply to cllady01]

While the thymus reaches maximum weight at puberty, T-Lymphocytes are continually made in the bone marrow throughout life and the thymus only gradually atrophies as we age. Read en.m.wikipedia.org/wiki/Thymus

Because you have a proliferation of B-Lymphocytes with CLL, that makes any percentage comparisons useless; you need to look at absolute counts.

CLL also tends to cause an inversion in the CD 4 (helper) and CD 8 (natural killer) ratio, but per your results, your ratio is still in the normal range.

More cllady01 , now that I can use my desktop PC: ncbi.nlm.nih.gov/pubmed/208...

Terry Hamblin discusses the impact of CLL on T-lymphocytes and CD4/CD8 ratio:

mutated-unmuated.blogspot.c...

Neil

[ThreeWs]

Thanks Neil,

The comment "To begin with, to test PRRL, the patient's immune system should not be too badly damaged by prior chemotherapy ...." coupled to the statement that "These PRRL are produced by invading pathogens such as bacteria, viruses and fungi and they can put our innate immune system on red alert within minutes." makes me wonder what difficulties this approach might encounter with immune dysfunction experienced by so many CLLers even without chemo? I would think the role of a functioning humoral or adaptive immune system would also be required to pull off an effective response.

All adds to the possibilities for at least understanding the complexity for immune response to cancers.

WWW

[Cllcanada Top Poster CURE Hero in reply to ThreeWs]

That is what Doxorubicin is... Red Devil ...a bacterial antibiotic toxin from an 13 century castle in Italy... there was a big push in the early 1950’s to look for new therapies... absolutely life savers...

Oh ya... it also turns your pee bright orange

en.m.wikipedia.org/wiki/Dox...

The earth in your garden hold cures, yet to be discouvered!

[mdsp7]

Interesting study; great picture!