CLL HSCs; CART19; SPs

[Guest guest]

Re: CLL HSCs - implications?

At 01:38 PM 9/12/2011, Al Janski wrote:

> " CLL and leukemic stem cells " (Dr.Hamblin's blog, Sept12)

>http://mutated-unmuated.blogspot.com/2011/09/cll-and-leukemic-stem-cells.html

SNIP........Dr. Hamblin wrote: " The concept if

that there is a damaged hemopoietic stem cell

(HSC) that feeds in to the tumor that does not

carry the same markers as the tumor and would

therefore not be susceptible to the type of

treatment that would be effective for the bulk of the tumor cells. "

One of the implications of Dr. Hamblin's insight

(that CLL HSCs would not be susceptible to

effective treatments for mature CLL cells) is

that it also applies to the recently published

CART19 Tcell immunotherapy (by June & coworkers;

in Porter et al. & Kalos, et al.; links below).

If indeed CLL HSCs are the predecessor cells to

mature CLL cells, then targeting CD19 with CART19

Tcells would not be expected to eliminate CLL,

because CLL HSCs are negative for CD19 (Kikushige et al., link below).

However, CART19 therapy may still be effective in

keeping the disease under control, by eliminating

the predecessor CLL cells (e.g. pro-Bcells),

which would evolve from CLL HSCs but are positive

for CD19. As such, for prolonged benefit, it

would be necessary for memory CART19 Tcells to

endure and remain competent to be activated by CD19 protein antigen.

Interestingly, CD19 positive " stem-like " CLL

cells have been isolated (by Gross et al. 2010,

and others). These " side-population " (SP) CLL

cells were chemoresistant to fludarabine, and

existed innately in patients, as well as being

increased ( " acquired " ) after fludarabine

treatment. These SP CLL cells may be derived

from maturation of CLL HSCs and may be

predecessors to some of the mature CLL cell

population, which might then be more

chemoresistant than other CLL cells derived from other precursor cells.

Further, isolated CLL SP cells have been used for

vaccination in patients ( et al., 2010),

eliciting a cytotoxic Tcell response that was

specific for CLL SP cells, rather than for mature

CLL cells. However, the anti-SP CLL T-cell

response was lost 4–6 weeks after vaccine

administration ceased. Apparently, a good memory

Tcell response, like that observed in the CART19

study, did not exist for this anti-SP response.

What is interesting is that et al. could

not detect any unique 'surface' antigen on SP CLL

cells that was not present on the larger

population of CLL cells. And it is noteworthy

that the process by which the stem-like SP CLL

cells are isolated involves first selecting for

cells containing proteins (i.e. " ABC transporter

proteins " ) that are 'not' on the cell surface,

but are 'intracellular' proteins that are known

to serve to pump out chemotherapeutic agents

(e.g. fludarabine) from a variety of cancer

cells, thus making them chemoresistant. Before

vaccination of patients, this knowledge was used

to enrich the SP CLL preparation by killing off

residual non-SP CLL cells with fludarabine.

The possibility exists that the immunogenicity of

SP cells was related to an 'intracellular'

protein antigen (e.g. an ABC transporter

protein), despite that notion being contrary to

conventional understanding of cellular

antigenicity. However, that convention may be changing.

Specifically, published last week, a paper (by

Guo et al.) demonstrated anti-tumor activity from

either exogenously administered antibodies or

from host-induced antibodies (i.e. vaccination)

against 'intracellular' tumor antigens. The

authors concluded that " This study suggests that

antibody-based therapy and vaccination against

cancer may be extended to a wider variety of

intracellular oncoproteins as therapeutic

targets. With cancer treatment becoming more

individualized, the ability to target a whole new

list of intracellular oncoproteins previously

thought to be untargetable by therapeutic

antibodies or vaccinations can expand the scope

for tailor-made cancer therapy as well as usher

in a new era of tailor-made cancer vaccines. "

Consequently, maybe it is not necessary that the

CART therapy technology target only surface

antigens (like CD19) on CLL cells, or surface

antigens on CLL HSCs, etc. Maybe better antigen

targets can be identified in the intracellular

space of CLL cells, such that benefits (like not

eliminating CD19 normal Bcells) can be achieved.

Al Janski

REFERENCES:

" Self-Renewing Hematopoietic Stem Cell Is the

Primary Target in Pathogenesis of Human Chronic

Lymphocytic Leukemia " ; Y. Kikushige et al.;

Cancer Cell 20, 246­259, August 16, 2011

ABSTRACT: http://www.sciencedirect.com/science/article/pii/S1535610811002595

" Chimeric Antigen Receptor-Modified T Cells in

Chronic Lymphoid Leukemia " ; D.L.Porter et al.; N Engl J Med 2011; 365:725-733

ABSTRACT:

<http://www.nejm.org/doi/pdf/10.1056/NEJMoa1103849>http://www.nejm.org/doi/pdf/1\

0.1056/NEJMoa1103849

" T Cells with Chimeric Antigen Receptors Have

Potent Antitumor Effects and Can Establish Memory

in Patients with Advanced Leukemia " ; M. Kalos, et

al.; Science Translational Medicine, Vol 3 Issue 95 95ra73, p.1-11.

FULL-TEXT: http://stm.sciencemag.org/content/3/95/95ra73.full.pdf

" B-chronic lymphocytic leukemia chemoresistance

involves innate and acquired leukemic side

population cells. " , E. Gross et al.; Leukemia 24, 1885-1892 (November 2010)

ABSTRACT: http://www.nature.com/leu/journal/v24/n11/full/leu2010176a.html

" Selective elimination of a chemoresistant side

population of B-CLL cells by cytotoxic T

lymphocytes in subjects receiving an autologous

hCD40L/IL-2 tumor vaccine " AE et al.; Leukemia (2010) 24, 563–572

FULL-TEXT:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836398/pdf/nihms165734.pdf

" Targeting Intracellular Oncoproteins with

Antibody Therapy or Vaccination " ; Ke Guo et al.;

Science Translational Medicine September 7, 2011 Vol 3 Issue 99 99ra85

ABSTRACT: http://stm.sciencemag.org/content/3/99/99ra85

PRESS RELEASE: http://www.sciencedaily.com/releases/2011/09/110908104205.htm

[Guest guest]

Dr. Keating of MDACC has given his viewpoint on Chimeric

Antigen Receptors (CARS) in CLL

Dr. Wierda answers some common questions on this

topic

May be of interest to some...

http://tinyurl.com/43v9cmq