comments on immunotherapy

[Guest guest]

Greetings,

This has not been a very good year for vaccine-based immunotherapy, when we

consider the " no difference " outcomes in two pivotal randomized vaccine

trials (Genitope and Favrille), and the demise of Biovest for reasons that

are not clear. The latter failure might be considered economic-based,

however the independent experts I queried were not enthused about the

results of the Biovest study either ... citing fuzzing reporting of the

patient population - that the analysis did not seem to account for all the

patients - the intent-to-treat population.

Still, we know from experence (a simple cold sore, auto-immune disease) that

the immune system is a very potent force that needs to be harnessed in the

fight against lymphomas and other cancers. Indeed, many experts think the

immune system already plays a vital role in even standard chemotherapy.

Reports from different groups on the microenvironment of the tumor suggests

that the profile of the normal interacting cells may determine the duration

of response to standard treatment. Also, noteworthy, is the very long time

to optimal response to radioimmunotherapy - well beyond the half life of the

treatment agent - suggests that the influence of treatment on immunity

against tumors is a key mechanism of action. Most likely, the unique

abnormal antigens of the dying and dead tumors are taken up by immune cells,

leading to a vaccinal effect ... adaptive (learned) immunity against the

surviving tumor cells. Similarly, some patients achieve durable remissions

from a single course of Rituxan, even if a minority. Likewise, from

chemotherapy.

Many experts have stated that vaccine therapy (injecting tumor-associated

antigens into the skin) without pretreatment is not likely to be effective,;

and I think we patients and caregivers have been reluctant to embrace or

accept that concept ... hoping, understandably, that we can have meaningful

benefit from treatment with zero risk. Not yet likely ... but someday?

Learning how tumors escape, or turn off immunity, seems a vital piece of the

solution, as is identifying new ways to enhance antibody-based therapy with

immune adjuvants or by simultaneously targeting the tumor escape mechanisms

with other agents.

Here's one approach that seems promising. The number of patients in this

pilot is too small, however, to form conclusions.

~ Karl

2008 Sep 15;112(6):2261-71. Epub 2008 May 28. Links

Blood. 2008 Sep 15;112(6):2172-3.

Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell

lymphoma using genetically modified autologous CD20-specific T cells.

http://www.ncbi.nlm.nih.gov/pubmed/18509084

n = 7 patients with indolent B-cell lymphoma or mantle cell

Adoptive immunotherapy with T cells expressing a tumor-specific chimeric

T-cell receptor is a promising approach to cancer therapy that has not

previously been explored for the treatment of lymphoma in human subjects.

We report the results of a proof-of-concept clinical trial in which patients

with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma

were treated with autologous T cells genetically modified by electroporation

with a vector plasmid encoding a CD20-specific chimeric T-cell receptor and

neomycin resistance gene.

Transfected cells were immunophenotypically similar to CD8(+) effector cells

and showed CD20-specific cytotoxicity in vitro.

Seven patients received a total of 20 T-cell infusions, with minimal

toxicities.

Modified T cells persisted in vivo 1 to 3 weeks in the first 3 patients, who

received T cells produced by limiting dilution methods, but persisted 5 to 9

weeks in the next 4 patients who received T cells produced in bulk cultures

followed by 14 days of low-dose subcutaneous interleukin-2 (IL-2)

injections.

Of the 7 treated patients, 2 maintained a previous complete response, 1

achieved a partial response, and 4 had stable disease. These results show

the safety, feasibility, and potential antitumor activity of adoptive T-cell

therapy using this approach. This trial was registered at

www.clinicaltrials.gov as #NCT00012207.

Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, SE,

Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD,

Riddell SR, Press OW.

Clinical Research Division of the Fred Hutchinson Cancer Research Center,

Seattle, WA 98109, USA. tillb@...